Biodegradable polymer—bioactive moiety conjugates

ABSTRACT

The invention relates to a biodegradable polymer comprising a plurality of releasable bioactive moieties, the releasable bioactive moieties being pendant from and covalently bonded to the biodegradable polymer backbone, wherein the biodegradable polymer backbone is formed from monomeric units that are each coupled via a biodegradable moiety, and wherein the bioactive moieties are capable of being released at a rate equal to or faster than the rate of biodegradation of the polymer backbone.

FIELD OF INVENTION

The present invention relates in general to polymer-bioactive moietyconjugates. In particular, the present invention relates tobiodegradable polymer-bioactive moiety conjugates, to methods forpreparing the polymers, and to monomer-bioactive moiety conjugatessuitable for preparing the polymers. The conjugates can be used ascoatings, scaffolds, stents and dressings for biomedical applicationsand in drug delivery devices. The invention also relates to a sustainedbioactive moiety delivery system comprising the conjugate, and also to amethod of delivering a bioactive moiety to a subject.

BACKGROUND

The targeted and controlled delivery of small molecule therapeutics isan area of considerable current interest. The site-specific delivery ofa therapeutic agent is a highly desirable feature for the treatment ofmany different conditions. In particular, products may be implanted inthe body of humans or animals which contain therapeutics. However, thereis a need to increase the efficacy and safety of such products.

One form of drug delivery involves the use of polymers to carry/retainthe drug moiety to/at a specific location. Several approaches to thishave been developed. Early controlled release methods involveddrug-polymer formulations that released the drug upon breakdown of thepolymer structure under physiological conditions, particularly throughoral administration. Later developments included the preparation ofdrug-polymer systems based on admixing or on covalent linking.

The admixture approach involves the preparation of a polymer drugmixture that is then compounded into a solid device. The linkingapproach involves using drug molecules as monomers in formation of thepolymer so that they form part of the polymer backbone, or covalentlyattaching drug molecules to a pre-formed polymer backbone. The linkingapproach gives rise to so called drug-polymer conjugate.

A major disadvantage of the admixture approach is that the release ofthe therapeutic agent is largely dependent on the breakdown of thepolymer structure. This results in poor control of the rate of drugrelease with the possibility of uncontrolled dosages being delivered.Furthermore, the amount of drug that can be loaded into an admixture islimited (typically <10% by weight).

The linking approach also has a number of problems associated with it.Where the drug forms part of the polymer backbone, the polymer structuremust degrade in order to release the drug. This will of course bedisadvantageous where it is desirable to at least maintain the polymerstructure while the drug is being released. Covalently attaching drugmolecules to a pre-formed polymer backbone can also be problematic. Inparticular, steric and thermodynamic constraints can affect the amountof bioactive moiety that can be covalently attached, and also impact onthe distribution of the bioactive moiety along the polymer backbone,which in turn can reduce control over the release of the bioactivemoiety.

An opportunity therefore remains to develop new polymer-bioactive moietyconjugates which address or ameliorate one or more disadvantages orshortcomings associated with existing materials and/or their method ofmanufacture, or to at least provide a useful alternative to suchmaterials and their method of manufacture.

SUMMARY OF THE INVENTION

The present invention therefore provides a biodegradable polymercomprising a plurality of releasable bioactive moieties, the releasablebioactive moieties being pendant from and covalently bonded to thebiodegradable polymer backbone, wherein the biodegradable polymerbackbone is formed from monomeric units that are each coupled via abiodegradable moiety, and wherein the bioactive moieties are capable ofbeing released at a rate equal to or faster than the rate ofbiodegradation of the polymer backbone.

An important feature of the invention is that the bioactive moieties arecapable of being released at a rate equal to or faster than the rate ofbiodegradation of the polymer backbone. By providing the biodegradablepolymer with such relative rates of release and biodegradation it canadvantageously release bioactive moiety without the polymer backboneundergoing substantial biodegradation.

It has been found that the biodegradable polymers according to theinvention are particularly useful in applications where controlleddelivery of bioactive moieties is required while maintaining thestructural integrity of the polymer backbone. For example, in providinga coating for use in infection control, the biodegradable polymersaccording to the invention retain the material properties of the polymerbackbone for periods of time sufficient to allow substantial delivery ofa bioactive moiety. The polymer backbone according to the invention isalso biodegradable such that after a period of time the backbonedegrades into biocompatible degradation products. The polymer backboneis preferably resorbable in vivo.

The biodegradable polymers in accordance with the invention may also bedefined in terms a molecular structure.

The invention therefore also provides a biodegradable polymer comprisingas part of its polymer backbone a plurality of moieties of generalformula (I):

where:

-   -   A and B, which are the same or different, represent the        remainder of the polymer backbone and (i) comprise one or more        —X—R(ZD)-Y— moieties as shown in formula (I), and (ii) are each        formed from monomeric units that are coupled via a biodegradable        moiety;    -   X and Y are each independently a biodegradable moiety;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a spacer moiety; and    -   D is a releasable bioactive moiety;        wherein the bioactive moieties (D) are capable of being released        at a rate equal to or faster than the rate of biodegradation of        the polymer backbone.

Each —X—R(ZD)-Y— moiety of the biodegradable polymers may be the same ordifferent.

Each X, Y, R, Z and D in a given —X—R(ZD)-Y— moiety of the biodegradablepolymers may be the same or different.

For avoidance of any doubt, the “moiety of general formula (I)” isintended to be a reference to:

with A and B being presented in formula (I) to (i) more clearly depictthat the “moiety” forms part of the polymer backbone, and (ii) definethe nature of the remainder of the polymer backbone.

As used herein the expression forming “part of the polymer backbone”means that the moiety of formula (I) (i.e. excluding A and B) is part ofthe string of atoms that are each connected so as to form the polymerchain (i.e. including A and B). In other words, the moiety of formula(I) is not pendant from the polymer backbone. Having said this, it willbe appreciated that groups Z and D in the moiety of formula (I) will bependant from the polymer backbone.

Examples of A and B are discussed in more detail below, but includepolyurethane, polyanhydride, polycarbonate, polyurea, polyamide,polyimide and polyester polymer chains, as well as copolymers thereof.

For example, the moiety of general formula (I) may in conjunction with asuitable comonomer form a repeat unit of a polyester, polyurethane orpolyanhydride as illustrated below in general formula (Ia), (Ib) and(Ic), respectively:

where R, Z and D are as herein defined and R^(x) is an optionallysubstituted alkyl, aryl or alkylaryl group, wherein for each repeat unitof the polyester each R, Z, D and R^(x) may be the same or different;

where R, Z and D are as herein defined and R^(x) is an optionallysubstituted alkyl, aryl or alkylaryl group, wherein for each repeat unitof the polyurethane each R, Z, D and R^(x) may be the same or different;

where R, Z and D are as herein defined and R^(x) is an optionallysubstituted alkyl, aryl or alkylaryl group, wherein for each repeat unitof the polyurethane each R, Z, D and R^(x) may be the same or different.

Those skilled in the art will appreciate that the respective ester,carbamate and anhydride moieties in general formulae (Ia), (Ib) and (Ic)are examples of the X and Y biodegradable moieties defined in generalformula (I).

In one aspect, the invention provides a biodegradable polymer-bioactivemoiety conjugate comprising as part of its polymer backbone a pluralityof moieties of general formula (Id):

wherein:

-   -   A and B, which may be the same or different, represent the        remainder of the polymer backbone and are selected from a        copolymer of polyurethane and polyester;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a linking group; and    -   D is a releasable bioactive moiety.

In some embodiments, the O atoms in the —O—R(ZD)-O— shown in generalformula (Id) may each independently form part of an ester or urethanemoiety as illustrated below where O* represents the O atom in the—O—R(ZD)-O— moiety:

In one embodiment, the O atoms in the —O—R(ZD)-O— each independentlyform part of an ester or urethane moiety.

In some embodiments, A and/or B may be a polyester. In that case, themonomeric units that are polymerised to form the polyester, typically adiacid and a diol, will each be coupled via a biodegradable estermoiety. A and/or B may also be a polyurethane. In that case, themonomeric units that are polymerised to form the polyurethane, typicallya diisocyanate and a diol, will each be coupled via a biodegradableurethane moiety. A and/or B may also be a poly(urethane-ester) formed bypolymerising a diisocyanate with a polyester macro-monomer or macromer.In that case, the polyester macromer will be formed from monomeric unitsthat are coupled via a biodegradable moiety (as discussed above), andthe polymerisation of it with the diisocyanate will give rise to thepoly(urethane-ester) having monomeric units that are all coupled via abiodegradable urethane or ester moiety. A and/or B may also be apoly(ester-urethane) formed by polymerising an isocyanate terminatedpolyurethane macro-monomer or macromer with an ester containing monomer,for example, an ester linked dimer of hydroxy acids. In that case, thepolyurethane macromer will be formed from monomeric units that arecoupled via a biodegradable moiety (as discussed above), and thepolymerisation of it with the ester monomer give rise to thepoly(ester-urethane) having monomeric units that are all coupled via abiodegradable urethane or ester moiety.

The biodegradable polymer in accordance with the invention may form partof or be formed into an article or device per se or can be presented asa coating on an existing article or device.

The biodegradable polymer provides an effective and efficient means fordelivering bioactive moieties to a subject.

In another aspect, the invention provides a method of delivering abioactive moiety to a subject, the method comprising administering tothe subject a biodegradable polymer in accordance with the invention.

Through the bioactive moiety release function of the biodegradablepolymers, the polymers can also advantageously function as or form partof a sustained bioactive moiety delivery system.

In further aspect, the invention therefore provides a sustainedbioactive moiety delivery system, the system comprising a biodegradablepolymer in accordance with the invention.

In one embodiment of the invention the releasable bioactive moieties arecovalently bonded to the polymer backbone via one or more spacermoieties.

In a further embodiment of the invention the biodegradable polymers havea content of releasable bioactive moieties relative to total polymer ofat least 10% by weight, preferably at least 20% by weight, morepreferably at least 30% by weight.

In a yet further embodiment of the invention the biodegradable polymerscontain two or more different releasable bioactive moieties.

In an even yet further embodiment of the invention the releasablebioactive moieties are capable of being released from the polymerbackbone such that they are unencumbered by excess molecular fragments.

In a preferred form of any one of the foregoing embodiments the releaseof bioactive moieties from the polymer backbone is substantiallycomplete prior to significant breakdown of the polymer backbone.

In a further preferred form of any one of the foregoing embodiments thepolymer backbone is substantially degradable to its constituent monomersunder in vivo conditions.

In an even further preferred form of any one of the foregoingembodiments the bioactive moiety is a drug moiety.

The invention also provides a biodegradable polymer-bioactive moietyconjugate prepared by polymerising a monomer-bioactive moiety conjugateof formula (II):

where:

-   -   X′ and Y′ are each hydroxyl;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a spacer moiety; and    -   D is a releasable bioactive moiety;        with a polyisocyanate and at least one selected from the group        consisting of a polyacid, a polyester and a polyester polyol.

In one embodiment, the monomer-bioactive moiety conjugate of formula(II) polymerises with a polyisocyanate and a polyester polyol.

Suitable polyisocyanates may be selected from the group consisting ofm-phenylene diisocyanate, p-phenylene diisocyanate, 2,4-toluenediisocyanate, 2,6-toluene diisocyanate, 1,6-hexamethylene diisocyanate,1,4-hexamethylene diisocyanate, 1,3-cyclohexane diisocyanate,1,4-cyclohexane diisocyanate, hexahydro-toluene diisocyanate and itsisomers, isophorone diisocyanate, dicyclo-hexylmethane diisocyanates,1,5-napthylene diisocyanate, 4,4′-diphenylmethane diisocyanate,2,4′diphenylmethane diisocyanate, 4,4′-biphenylene diisocyanate,3,3′-dimethoxy-4,4′-biphenylene diisocyanate,3,3′-dimethyl-diphenylpropane-4,4′-diisocyanate, 2,4,6-toluenetriisocyanate, 4,4′-dimethyl-diphenylmethane-2,2′,5,5′-tetraisocyanate,polymethylene polyphenhyl polyisocyanates and alkyl esters of lysinediisocyanate (preferably ethyl ester of lysine diisocyanate), andcombinations thereof. Preferred polyisocyanates include1,6-hexamethylene diisocyanate and alkyl esters of lysine diisocyanate,preferably ethyl ester of lysine diisocyanate.

Suitable polyacids may be selected from the group consisting of oxalicacid, fumaric acid, maleic acid, succinic acid, glutaric acid, adipicacid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalicacid, dodecanediacid, isophthalic acid, terephthalic acid,dodecylsuccinic acid, napthalene-2,6-dicarboxylic acid,naphthalene-2,7-dicarboxylic acid, cyclohexane dicarboxylic acid,itaconic acid, malonic acid, and mesaconic acid. Preferred polyacidsinclude maleic acid and succinic acid.

Suitable polyester polyols may be selected from the group consisting ofpolycaprolactone diol (PCLD), poly(DL lactide) (DLLA) and poly(lacticacid-co-glycolic acid) (PLGA), and combinations thereof.

The invention also provides a method for preparing a biodegradablepolymer according to the invention, said method comprising the step ofpolymerising a monomer-bioactive moiety conjugate of formula (II):

where:

-   -   X′ and Y′ are each independently functional groups that (a) are        capable of undergoing polymerisation with monomer having        compatible chemical functionality, and (b) react with the        compatible chemical functionality to afford a biodegradable        moiety;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a spacer moiety; and    -   D is a releasable bioactive moiety;        with at least one monomer comprising compatible chemical        functionality.

In a further aspect there is provided a method for preparing thebiodegradable polymer of the present invention by providing at least onefirst monomer comprising at least one releasable bioactive moiety and atleast one polymerisable moiety; optionally providing at least one secondmonomer comprising at least one polymerisable moiety reactive with atleast one polymerisable moiety of said first monomer; polymerising saidfirst monomer and optionally said second monomer optionally in thepresence of one or more spacer moieties comprising two or morefunctionalities under conditions which are substantially non-interferingto the therapeutic efficacy of the bioactive moieties.

In another aspect, the invention also provides a process for preparing abiodegradable polymer-bioactive moiety conjugate comprising as part ofits polymer backbone a plurality of moieties of general formula (Id):

wherein:

-   -   A and B, which may be the same or different, represent the        remainder of the polymer backbone and are selected from a        copolymer of polyurethane and polyester;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a linking group; and    -   D is a releasable bioactive moiety;        said process comprising the step of polymerising a        monomer-bioactive moiety conjugate of formula (IIa):

wherein:

-   -   R, Z and D are as defined above;        with at least one other monomer comprising compatible chemical        functionality.

There is yet further provided a use of the biodegradable polymers of theinvention in the preparation of an implantable scaffold, stent or abiomedical coating or dressing or an adhesive.

There is even yet further provided a method of using the biodegradablepolymer of the invention to deliver a bioactive moiety, preferably adrug moiety.

The present invention also provides a monomer-bioactive moiety conjugatecomprising: a) one or more releasable bioactive moieties; b) two or morepolymerisable moieties; wherein one or more of the releasable bioactivemoieties are capable of being released from the monomer before or afterpolymerisation under conditions which are non-interfering to thetherapeutic efficacy of the bioactive moieties.

The monomer-bioactive moiety conjugate in accordance with the inventionmay also be defined in terms a molecular structure.

In another aspect, the invention therefore provides a monomer-bioactivemoiety conjugate that is suitable for use in preparing a biodegradablepolymer-bioactive moiety conjugate, the monomer-bioactive moietyconjugate having a structure of general formula (II):

where:

-   -   X′ and Y′ are each independently functional groups that (a) are        capable of undergoing polymerisation with monomer having        compatible chemical functionality so as to form a biodegradable        polymer, and (b) react with the compatible chemical        functionality to afford a biodegradable moiety;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a spacer moiety; and    -   D is a releasable bioactive moiety.

In one embodiment, the two or more polymerisable moieties of themonomer-bioactive moiety conjugate (e.g. X′ and Y′ of general formula(II)) may each be independently selected from hydroxyl, amine,carboxylic acid, isocyanate, and carboxylic acid halide.

In another aspect, the invention provides a monomer-bioactive moietyconjugate that is suitable for use in preparing a biodegradablepolymer-bioactive moiety conjugate, the monomer-bioactive moietyconjugate having a structure of general formula (IIa):

wherein:

-   -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a linking group; and    -   D is a releasable bioactive moiety.

The monomer-bioactive moiety conjugates of the invention have been foundto be particularly versatile and can advantageously be polymerised withone or more monomers using techniques well known in the art.

In another aspect the invention provides a process for preparing amonomer-bioactive moiety conjugate that is suitable for use in preparinga biodegradable polymer-bioactive moiety conjugate, themonomer-bioactive moiety conjugate having a structure of general formula(IIa):

wherein:

-   -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a linking group; and    -   D is a releasable bioactive moiety,        said process comprising covalently coupling a linking precursor        group Z′ in a compound of formula (VI):

-   -   wherein:    -   P¹ and P² are each independently H, a protecting group, or P¹        and P² together form a protecting group; and    -   R is as defined above,        with a group selected from D or D-Z″,    -   wherein:    -   D is a bioactive moiety in protected or unprotected form or        prodrug thereof; and    -   Z″ is a linking precursor group,        wherein the coupling of Z′ with D, or the coupling of Z′ with Z″        in the group D-Z″, forms the

moiety in the conjugate of formula (IIa),and where P¹ and/or P² are protecting groups said process furthercomprises the step of removing the protecting group or groups.Z′ and Z″ (when present) are each linking precursor groups which affordthe linking group Z in the monomer-bioactive moiety conjugate of formula(IIa).

In some embodiments, Z′ is a moiety comprising a functional group suchas a carboxylic acid, acid halide, primary amino, secondary amino,hydroxy group, thiol group, phosphate group or sulphate group thatcouples to D or couples to Z″ in the group D-Z″.

In some embodiments, Z″ is a moiety comprising a functional group suchas a carboxylic acid, acid halide, primary amino, secondary amino,hydroxy group, thiol group, phosphate group or sulphate group thatcouples to

When preparing monomers of general formula (IIa), it may also bedesirable to modify the bioactive moiety (D) so as to facilitate itsconjugation with compounds of formula (VI). For example, where Z′ informula (VI) comprises a hydroxy group, ester formation through reactionof this hydroxy group with a carboxylic acid group in D can in somecases prove difficult. Under these circumstances, ester formation may befacilitated by first converting the carboxylic acid group in D into anacid halide (e.g. acid chloride) group and then reacting the acid halidegroup with the hydroxy group.

In other embodiments, the bioactive moiety (D) may first undergoreaction with an appropriate reagent to form the conjugate D-Z″. Forexample, reaction under appropriate conditions of a carboxylic acidfunctionality on D with a diol, such as 1,6-hexanediol, affords D-Z″where Z″ is a linking precursor group derived from 1,6-hexanediol.Subsequent coupling of the remaining free alcohol from 1,6-hexanediolwith a functional group on Z′, such as an acid halide, affords a monomerof formula (IIa) comprising a linking group (Z) formed from the linkingprecursor groups Z′ and Z″.

The skilled worker will be familiar with techniques that may be used topromote reactions between functional groups of complementary reactivity,such as between a carboxylic acid and a hydroxy group. For example,coupling agents such as those mentioned in Tetrahedron Volume 60, Issue11, 8 Mar. 2004, pages 2447-2467, could be employed (see further detailbelow).

Further aspects of the invention appear below in the detaileddescription of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention will herein be illustrated by wayof example only with reference to the accompanying drawings in which:

FIG. 1 illustrates weight loss of biodegradable polymers afterincubation in physiological conditions at 37° C. demonstratingbioerosion;

FIG. 2 illustrates in vitro release of Levofloxacin and thecorresponding Levofloxacin containing monomer,Levofloxacin-monoglyceride, from a Levofloxacin-polyurethane conjugateproduced from a 1:1 molar ratio of Levofloxacin monoglyceride andhexamethyl diisocyanate (Example 20);

FIG. 3 illustrates in vitro release of Levofloxacin from biodegradablepolymers described in examples 25, 26, 27 and 28 showing cumulativeamount of levofloxacin released versus time;

FIG. 4 illustrates antimicrobial activity of levofloxacin-conjugatepolymer films against S. aureus. Six mm diameter discs coated on asingle side (10% w/w levofloxacin—example 36) (▴) of differentgeometries (57% w/w levofloxacin—example 20) (●—disc; ▪—square) weretransferred daily to a freshly inoculated bacterial lawn, incubated andthe zone of inhibition measured. Data are the mean zone of inhibition(mm)±standard error measured from six discs;

FIG. 5 illustrates in vitro release of Levofloxacin from thebiodegradable polymer described in example 37 showing cumulative amountof levofloxacin released versus time;

FIG. 6 illustrates in vitro release of Levofloxacin from thebiodegradable polymer described in example 37 showing percentage oflevofloxacin released from the polymer conjugate versus time;

FIG. 7 illustrates in vitro release of Levofloxacin from thebiodegradable polymer described in example 37 showing amount oflevofloxacin released per 24 hours versus time;

FIG. 8 illustrates in vitro release of Valproic Acid from polymersdescribed in CE1, 13, 14, 16 and 17 showing cumulative amount ofValproic Acid released versus time;

FIG. 9 illustrates a simplified structure of a biodegradable polymer inaccordance with the invention;

FIG. 10 illustrates a simplified structure of a biodegradable polymeraccording to the invention with multiple drugs; and

FIG. 11 illustrates a simplified structure of a biodegradable polymeraccording to the invention with multiple linker types and drugs.

DETAILED DESCRIPTION OF THE INVENTION

The terms “labile” and “releasable” may be used herein synonymously.

Polymers having bioactive moieties covalently attached thereto are oftenreferred to in the art as “polymer-bioactive moiety conjugates”. It maytherefore be convenient to refer to a biodegradable polymer of theinvention as biodegradable polymer-bioactive moiety conjugate or simplyas a conjugate.

A biodegradable polymer of the invention may also be described as beinga “functionalised” biodegradable polymer by virtue of the bioactivemoieties being covalently attached to or “functionalising” the polymerbackbone.

An important feature of the conjugates in accordance with the inventionis that they are “biodegradable”. By being “biodegradable” in thecontext of the invention is meant that polymer or polymer backboneundergoes with the passage of time substantial degradation underphysiological conditions or in a biological environment. In other words,the polymer backbone has a molecular structure that is susceptible tobreak down (i.e. a reduction in molecular weight) by chemicaldecomposition in a biological environment (e.g. within a subject or incontact with biological material such as blood, tissue etc), as opposedto physical degradation. Such chemical decomposition will typically bevia the hydrolysis of labile or biodegradable moieties that form part ofthe molecular structure of the backbone. Accordingly, such labile orbiodegradable moieties will generally be susceptible to hydrolyticcleavage.

Reference herein to biological material such as “biological tissue” isintended to include cells or tissue in vivo (e.g. cells or tissue of asubject) and in vitro (e.g. cultured cells).

By being biodegradable, the conjugates in accordance with the inventioncan advantageously be used to release bioactive moieties, for examplewithin a subject, without the need to subsequently remove the remainingconjugate structure from the subject.

An important feature of the biodegradable properties of the polymers isits backbone is formed from monomeric units that are each coupled via abiodegradable moiety. By having such characteristics, the polymers inaccordance with the invention can advantageously biodegrade intosubstantially non-toxic residues.

For example, the —X—R(ZD)-Y— moiety as shown in formula (I) is attachedto the remainder of the polymer backbone (represented by A and B) via abiodegradable moieties X and Y, and A and B in their own right are eachformed from monomeric units that are coupled via a biodegradable moiety.

As used herein the expression “biodegradable moiety” is intended to meana moiety that can undergo chemical decomposition under physiologicalconditions or in a biological environment. Such chemical decompositionwill typically be via hydrolysis. In other words, the biodegradablemoiety with be susceptible to hydrolytic cleavage. In the context of thepresent invention, the biodegradable moieties function to link or couplethe monomeric units that form the polymer backbone. Accordingly, it willbe appreciated that the biodegradable moieties give rise to thebiodegradable property of the polymer.

Those skilled in the art will appreciate the type of moieties that aretypically susceptible to hydrolytic cleavage under physiologicalconditions or in a biological environment. Such moieties (represented byX and Y in general formula (I)) may include amide, urethane (carbamate),ester, anhydride, urea and carbonate. The biodegradable polymers inaccordance with the invention may include a combination of suchmoieties.

The terms “carmbamate” and “urethane” referred to herein are usedinterchangeably. A person skilled in the art would understand that theseterms “carmbamate” and “urethane” each refer to a —NC(═O)O— moiety.

In one embodiment, X and Y of all —X—R(ZD)-Y— moieties in thebiodegradable polymer are each independently an ester or urethanemoiety.

Those skilled in the art will appreciate the type of moieties that arenot typically susceptible to hydrolytic cleavage in a biologicalenvironment. Such moieties may include carbonyl, siloxane, sulfone,ether, olefin (i.e. C—C, e.g. alkylene, alkenylene and alkynylene) andhalogenated olefin.

As noted above, the biodegradable polymer in accordance with theinvention will only include monomeric units that are coupled to eachother via a biodegradable moiety. By “monomeric units” is meant thebuilding blocks that are polymerised to form the polymer. The monomericunits may in their own right be macro-monomeric units (i.e. monomericunits that are typically low molecular weight polymers and containmonomeric units in their own right—commonly referred to as macromers).Where the monomeric units are macromers, they too must be formed onlyfrom monomeric units that are coupled via a biodegradable moiety.

For example, the biodegradable polymer may be a polyester. In that case,the monomeric units that are polymerised to form the polyester,typically a diacid and a diol, will each be coupled via a biodegradableester moiety. The biodegradable polymer may also be a polyurethane. Inthat case, the monomeric units that are polymerised to form thepolyurethane, typically a diisocyanate and a diol, will each be coupledvia a biodegradable urethane moiety. The biodegradable polymer may alsobe a poly(urethane-ester) formed by polymerising a diisocyanate with apolyester macromer. In that case, the polyester macromer will be formedfrom monomeric units that are coupled via a biodegradable moiety (asdiscussed above), and the polymerisation of it with the diisocyanatewill give rise to the poly(urethane-ester) having monomeric units thatare all coupled via a biodegradable urethane or ester moiety. Thebiodegradable polymer may also be a poly(ester-urethane) formed bypolymerising an isocyanate terminated polyurethane macro-monomer ormacromer with an ester containing monomer, for example, an ester linkeddimer of hydroxy acids such as lactic acid and glyolic acid. In thatcase, the polyurethane macromer will be formed from monomeric units thatare coupled via a biodegradable moiety (as discussed above), and thepolymerisation of it with the ester monomer give rise to thepoly(ester-urethane) having monomeric units that are all coupled via abiodegradable urethane or ester moiety.

Accordingly, it will be appreciated that the present invention is notintended to embrace the situation where the biodegradable polymercomprises monomeric units that are coupled to each other via anon-biodegradable moiety. For example, the biodegradable polymer can notbe a polyether. The biodegradable polymer also can not be a polymercomprising a polyether such as a poly(urethane-ether) orpoly(ester-ether) formed by polymerising a diisocyanate and diacid,respectively, with a polyether macromer (e.g. polyalkyleneglycols suchas polyethyeneglycol and polypropyleneglycol). In that case, thepolyether macromer will be formed from monomeric units (e.g. —(OR)n-)that are coupled via a non-biodegradable moiety (i.e. an ether), and thepolymerisation of it with the diisocyanate or diacid will give rise tothe poly(urethane-ether) or poly(ester-ether), respectively, that hasmonomeric units coupled via non-biodegradable moieties.

The biodegradable characteristics of the conjugates in accordance withthe invention advantageously enable its polymer backbone to degrade intosubstantially non-toxic residues. This is in contrast withpolymer-bioactive moiety conjugates that comprise within their polymerbackbone a non-biodegradable polymer segment such as a polyether orpolyvinyl that may give rise to toxic residues. For example, somepolyethers are known to be toxic to humans and animals.

Furthermore, low molecular weight diols such as C₂₋₁₀, C₂₋₆ or C₂ diols(e.g. ethylene glycol) can also be toxic to humans and animals. Lowmolecular weight diols are commonly used as comonomers or chainextenders in the manufacture of polymers such polyurethanes andpolyesters. If such diols are used in preparing the biodegradablepolymers of the invention they can subsequently be liberated upon itsbiodegradation. Accordingly, it can be desirable to limit their use inthe biodegradable polymers of the invention. In contrast, higheralcohols such as triols are typically less toxic to humans and animals.

In one embodiment, the biodegradable polymers of the invention comprisepolymerised residues of a diol and less than 25 mol %, less than 10 mol%, or less than 5 mol % of those polymerised residues are derived from alow molecular weight diol (C₂₋₁₀, C₂₋₆ or C₂ diol).

In a further embodiment, the biodegradable polymers of the inventioncomprise substantially no polymerised residues of a low molecular weightdiol (C₂₋₁₀, C₂₋₆ or C₂ diol).

In still a further embodiment, where the biodegradable polymers of theinvention are prepared using diol monomer, less than 25 mol %, less than10 mol %, or less than 5 mol % of that monomer comprises a low molecularweight diol (C₂₋₁₀, C₂₋₆ or C₂ diol).

In yet a further embodiment, where the biodegradable polymers of theinvention are prepared using diol monomer, that monomer comprisessubstantially no low molecular weight diol (C₂₋₁₀, C₂₋₆ or C₂ diol).

The mol % diol/diol residue values referred to herein are those relativeto the total moles of diol/diol residue.

In addition to the polymer backbone of the conjugates beingbiodegradable, it has covalently attached to it in pendant form aplurality of releasable bioactive moieties.

By the bioactive moieties being in “pendant form” is meant that they donot directly form part of the polymer backbone and as such can bereleased without causing a reduction in the chain length of the polymerbackbone. This is more clearly illustrated by general formula (I).

By the bioactive moieties being “releasable”, “labile”, or “capable ofbeing released” is meant that they can be covalently decoupled orcleaved from the polymer backbone so as to present in a biologicallyactive form. In the context of general formulae I and II above, themoiety will therefore be capable of being released or cleaved from the Zgroup to afford D per se. Release of the moieties will generally bepromoted by the conjugates being exposed to physiological conditions ora biological environment.

The ability of the bioactive moieties to be releasable will generally beas result of them being coupled in pendant form via a biodegradablemoiety either directly or through a spacer moiety to the polymerbackbone. Hydrolytic cleavage of the biodegradable moiety as hereindescribed therefore will promote release of the bioactive moiety.Further detail in relation to this is discussed below.

The biodegradable polymers in accordance with the invention canadvantageously be prepared such that they are suitable foradministration to a subject (i.e. suitable for in vivo applications).

According to one embodiment there is provided a method of delivering abioactive moiety to a subject, the method comprising administering tothe subject a biodegradable polymer in accordance with the invention.

By the biodegradable polymer being “suitable” for administration to asubject is meant that administration of the conjugate to a subject willnot result in unacceptable toxicity, including allergenic responses anddisease states.

By the term “subject” is meant either an animal or human subject. By“animal” is meant primates, livestock animals (including cows, horses,sheep, pigs and goats), companion animals (including dogs, cats, rabbitsand guinea pigs), and captive wild animals (including those commonlyfound in a zoo environment). Laboratory animals such as rabbits, mice,rats, guinea pigs and hamsters are also contemplated as they may providea convenient test system. Generally, the subject will be a humansubject.

By “administration” of the conjugate to a subject is meant that thecomposition is transferred to the subject such that the bioactive agentwill be released. Provided the bioactive agent can be released, there isno particular limitation on the mode of administration, but this willgenerally be by way of oral, parenteral (including subcutaneous,intradermal, intramuscular, intravenous, intrathecal, and intraspinal),inhalation (including nebulisation), buccal, pulmonary, aural, ocular,nasal, topical, rectal and vaginal modes.

The biodegradable polymers may be provided in particulate form andblended with a pharmacologically acceptable carrier to facilitateadministration. By “pharmacologically acceptable” is meant that thecarrier is suitable for administration to a subject in its own right. Inother words, administration of the carrier to a subject will not resultin unacceptable toxicity, including allergenic responses and diseasestates. The term “carrier” refers to the vehicle with which theconjugate is contained prior to being administered.

As a guide only, a person skilled in the art may consider“pharmacologically acceptable” as an entity approved by a regulatoryagency of a federal or state government or listed in the US Pharmacopeiaor other generally recognised pharmacopeia for use in animals, and moreparticularly humans.

Suitable pharmacologically acceptable carriers are described in Martin,Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co.,Easton, Pa., (1990), and include, but are not limited to, liquids thatmay be sterilised such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soya beanoil, mineral oil, sesame oil, and the like.

The biodegradable polymers may also form part of or be formed into anarticle or device, or be applied as a coating on an article or device,and implanted in a subject. By being “implanted” is meant that thearticle or device is totally or partly introduced medically into asubjects body, or by medical intervention into a natural orifice of asubject, and which is intended to remain there after the procedure.

Suitable dosage amounts of the bioactive moiety and dosing regimens ofthe biodegradable polymers can be determined by a physician and maydepend on the particular condition being treated, the rate of release ofthe moiety form the polymer backbone, the severity of the condition aswell the general age, health and weight of the subject.

Dosing may occur at intervals of minutes, hours, days, weeks, months oryears or continuously over any one of these periods. Suitable dosages ofthe bioactive moiety per se (i.e. that which is to be release from thepolymer backbone within a given time frame) may lie within the range ofabout 0.1 mg per kg of body weight to 1 g per kg of body weight perdosage. The dosage may be in the range of 1 μg to 1 g per kg of bodyweight per dosage, such as is in the range of 1 mg to 1 g per kg of bodyweight per dosage. In one embodiment, the dosage may be in the range of1 mg to 500 mg per kg of body weight per dosage. In another embodiment,the dosage may be in the range of 1 mg to 250 mg per kg of body weightper dosage. In yet another embodiment, the dosage may be in the range of1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg perbody weight per dosage.

The biodegradable polymers in accordance with the invention may beadministered in a single dose or a series of doses.

Dosage forms adapted for administration by the above modes may also beformulated with the biodegradable polymer as one of the components ofthe dose formulation. In the case of ocular, aural or nasaladministration the biodegradable polymer may be a component of a drop,cream or ointment or take the form of an implant, ointment or gel. Inthe case of oral administration the biodegradable polymer could take theform of or be a component in a tablet, capsule or liquid. In the case oftopical administration the biodegradable polymer could take the form ofor be a component in a cream, ointment, gel or liquid (e.g. eye drop).Parenteral administration would involve the biodegradable polymer to bepart of or take the form of an injectable product or implantable device(e.g. coating on a pacemaker) that can be administered subcutaneously,intramuscularly, intravenously or by direct surgical placement withinthe body.

The form of the biodegradable polymer may be adjusted to be suited tothe required application such as a coating, film, pellet, capsule,fibres, laminate, foam etc. The difference in the form of thebiodegradable polymer provides a means to alter the release profile ofthe bioactive moiety. For example the amount of polymer and bioactivemoiety may be the same in two different structures e.g. (a) polymerfilm, and (b) woven multifilament mat. The differences in the surfacearea to volume, rates of hydration and diffusion paths from thedifferent physical structures can result in different rates of bioactivemoiety release from essentially the same polymer.

The adjustment of the form of the polymer to suit the application andfurther to adjust the form to further control the bioactive moietyrelease profile provide an additional advantage over purelycompositional and polymer structural means to control the releaseprofile of the bioactive moiety.

Some of the compositional/structural means to control the release of thebioactive moiety include: controlling the loading of the bioactive;composition of the other comonomers to adjust criteria such ashydrophobicity, flexibility, susceptibility to degradation, ability ofthe fragments to autocatalyse the polymer degradation, thermal stabilityof the polymer, mouldability, polymer solubility to assist casting etc.

Additionally, the ability to produce the biodegradable polymers into arange of forms provide a means to produce three dimensional structuresthat can be beneficial is providing structural integrity to theirapplication as well as providing a means to control cell growth bycontrol of the placement of the conjugate in structures to allow releaseof the bioactive moiety at specific places (e.g. fibre coating or fibresin a stent to prevent or control restinosis) Other examples include theability of the structures to be formed into porous three dimensionalstructures to control cell phenotype as well as the filter or limitdifferent types of cell bodily fluid ingress.

The biodegradable polymers in accordance with the invention may also beused in in vitro applications such as assays. Such in vitro applicationscould involve the use of the biodegradable polymers as a coating of areaction chamber that would have an affect on chamber constituents (e.g.encourage cell growth, discourage growth of contaminating organisms,etc) or as a component within the assay to provide a source of thebioactive moiety (e.g. as an antigen for an ELIZA test).

The use of the biodegradable polymers for in vitro applications couldallow the use of the formed polymer to provide a host for bio-signals,essential additives drugs etc for the interaction controlled growth,cell segregation, controlled cell differentiation etc of cells/tissuecomponents etc.

The formed biodegradable polymer could be made into a structure that iscompatible with cell culture ware or in vitro devices used to act asindicators etc of certain conditions. The forms of the conjugate couldrange from simple pellets or films through to multilayer films, fibrousknitted, woven or electrospun structures, printed, spun cast, depositedor cast structures through to foams or composite type structures havingmultiple forms or components.

The expression “bioactive moiety” (also represented as “D” in certainformulae herein) is used to define any substance that is of medical orveterinary therapeutic, prophylactic or diagnostic utility capable offorming a conjugate in accordance with the invention. For example abioactive moiety may be a drug or therapeutically active agent,including pharmacologically active agents (e.g. receptor binding agonistor antagonists, cytotoxic agents), pharmacologically inactive agents(e.g. antibiotics) and prodrugs thereof. The bioactive moiety willgenerally be a substance (e.g. pharmaceutical substance) for therapeuticuse whose application (or one or more applications) involves: a chemicalinteraction, or physicochemical interaction, with a subject'sphysiological system; or an action on an infectious agent, or on a toxinor other poison, in subject's body; or with biological material such ascells in vitro.

As used herein, a “therapeutic agent” refers to a bioactive moiety that,when administered to a subject, will cure, or at least relieve to someextent, one or more symptoms of, a disease or disorder.

As used herein, a “prophylactic agent” refers to a bioactive moietythat, when administered to a subject either prevents the occurrence of adisease or disorder or, if administered subsequent to a therapeuticagent, prevents or retards the recurrence of the disease or disorder.

Upon being released, the bioactive moiety will either be bioactive orwill be converted in vivo or in vitro to a bioactive moiety (e.g. as inthe case of a prodrug). Despite the bioactive moiety being releasablefrom the monomer of formula II, it will be appreciated that theintention of the present invention is for the moiety to be releasedafter the monomer has been polymerised to form polymer.

The bioactive moiety may be released from the biodegradable polymer suchthat it provides for a sustained bioactive delivery system. Such adelivery system may in its simplest form be the polymer provided in adesired shape, for example a pellet or more intricate shape. To promotesurface area contact of the polymer under physiological conditions orwith a biological environment, it may also be provided in the form of afoamed product or a coating on substrate.

By “sustained bioactive moiety delivery” is meant that the bioactivemoiety is released from the biodegradable polymer over a period of time,for example over a period of 10 or more minutes, 30 or more minutes, 60or more minutes, 2 or more hours, 4 or more hours, 12 or more hours, 24or more hours, 2 or more days, 5 or more days, 10 or more days, 30 ormore days, 2 or more months, 4 or more months or over 6 or more months.

In order for the bioactive moiety (also denoted by D in certain formulaeherein) to be released, the covalent bond that (a) directly couples themoiety to the polymer backbone, or (b) directly couples the moiety to aspacer moiety which itself is attached to the polymer backbone; (e.g.the covalent bond between D and the Z group in formula (I)), will ofcourse need to be cleaved. For convenience, this covalent bond may bereferred to as the “coupling” covalent bond.

In one embodiment the coupling covalent bond is not a carbon-carbonbond. In such an embodiment, the coupling covalent bond will generallyform part of a functional group selected from: esters; amides;anhydrides; imides; carbonates; peroxides; peroxyesters; phosphates;thioesters; sulfates; disulfides; carbamates; ethers; siloxanes; azo;orthoesters; phosphonates; peroxy; and boronate esters. Of thesefunctional groups, anhydrides, esters, imides, carbonates, carbamates,and boronate esters are preferred.

Cleavage of the coupling covalent bond can be promoted hydrolytically(i.e. hydrolytic cleavage) and may take place in the presence of waterand an acid or a base. In some embodiments the cleavage may take placein the presence of one or more hydrolytic enzymes or other endogenousbiological compounds that catalyze or at least assist in the cleavageprocess. For example, an ester bond may be hydrolytically cleaved toproduce a carboxylic acid and an alcohol, and an amide bond may behydrolytically cleaved to produce a carboxylic acid and an amine. Thoseskilled in the art will appreciate that such cleavage amounts to thehydrolytic cleavage of the biodegradable moieties discussed herein.Accordingly, the bioactive moiety (D) may also be described as beingcoupled to the polymer backbone, optionally through a spacer moiety (Z)via a biodegradable moiety.

As indicated above, on being released the bioactive moiety may be in theform of a prodrug. As used herein, the term “prodrug” refers to aderivative of a bioactive moiety, wherein the derivative may have littleor none of the activity of the bioactive moiety per se yet is capable ofbeing converted in vivo or in vitro into a bioactive moiety. An exampleof such derivatisation is the acetylation of one or more hydroxyl groupson a bioactive moiety, such that subsequent to being released in vivothe released prodrug is deactylated to produce the bioactive moiety.

The terms “spacer”, “spacer group” or “spacer moiety” refer to an atomor any straight chain or branched, symmetric or asymmetric compoundcapable of linking or coupling the bioactive moiety to a monomer or apolymer backbone.

For example, in the structures of formulae (I), (Ia), (Ib), (Ic), (Id),(II), and (IIa), the bioactive moiety (D) is coupled to R through aspacer moiety denoted by Z. Thus, “spacer”, “spacer group” or “spacermoiety” refers to a substituent which is generally divalent and thatcouples D to R. As outlined above, the covalent bond between the spacermoiety and the bioactive moiety is cleavable so that the bioactivemoiety is releasable.

Examples of suitable spacer moieties include the divalent form of agroup selected from oxy (—O—), alkyl, alkenyl, alkynyl, aryl, acyl(including —C(O)—), carbocyclyl, heterocyclyl, heteroaryl, alkyloxy,alkenyloxy, alkynyloxy, aryloxy, acyloxy, carbocyclyloxy,heterocyclyloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio,arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio,alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl,alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl,alkynyloxyalkyl, aryloxyalkyl, alkyl acyloxy, alkyl oxyacylalkyl,alkylcarbocyclyloxy, alkylheterocyclyloxy, alkylheteroaryloxy,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl,alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio,alkylheteroarylthio, alkylalkenylalkyl, alkyl alkynylalkyl,alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl,arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclyl,arylheterocyclyl, arylheteroaryl, alkenyloxyaryl, alkynyloxyaryl,aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, arylheterocyclyloxy,arylheteroaryloxy, alkylthioaryl, alkenylthioaryl, alkynylthioaryl,arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio,and arylheteroarylthio, wherein where present the or each —CH₂— group inany alkyl chain may be replaced by a divalent group independentlyselected from —O—, —OP(O)₂—, —OP(O)₂O— —S—, —S(O)—, —S(O)₂O—, —OS(O)₂O—,—N═N—, —OSi(OR^(a))₂O—, —Si(OR^(a))₂O—, —OB(OR^(a))O—, —B(OR^(a))O—,—NR^(a)—, —C(O)—, —C(O)O—, —OC(O)O—, —OC(O)NR^(a)— and —C(O)NR^(a)—,where the or each R^(a) may be independently selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl,arylalkyl, and acyl. The or each R^(a) may also be independentlyselected from hydrogen, C₁₋₁₈alkyl, C₁₋₁₈alkenyl, C₁₋₁₈alkynyl,C₆₋₁₈aryl, C₃₋₁₈carbocyclyl, C₃₋₁₈heteroaryl, C₃₋₁₈heterocyclyl, andC₇₋₁₈arylalkyl.

The spacer moiety may be branched. In some embodiments where the spacermoiety is branched, two or more releasable bioactive moiety may beappended to the spacer moiety.

In the lists above defining groups (generally divalent) from which theor each spacer moiety may be selected, each alkyl, alkenyl, alkynyl,aryl, carbocyclyl, heteroaryl, and heterocyclyl moiety may be optionallysubstituted. For avoidance of any doubt, where a given spacer moietycontains two or more of such moieties (e.g. alkylaryl), each of suchmoieties may be optionally substituted with one, two, three or moreoptional substituents as herein defined.

In the lists above defining groups (generally divalent) from which theor each spacer moiety may be selected, where a given spacer moietycontains two or more subgroups (e.g. [group A] [group B]), the order ofthe subgroups is not intended to be limited to the order in which theyare presented. Thus, a spacer moiety with two subgroups defined as[group A][group B] (e.g. alkylaryl) is intended to also be a referenceto a spacer moiety with two subgroups defined as [group B][group A](e.g. arylalkyl).

The biodegradable polymer of present invention can be readily preparedusing monomer—bioactive moiety conjugates, such as those of generalformula (II) or (IIa). Such monomers can themselves be prepared usingcommonly available reagents. Examples of such reagents that may be usedto construct the spacer moiety (e.g. Z) include linear or branchedhydrocarbons substituted with two or more reactive functional groupssuch as alcohols, primary and secondary amines, carboxylic acids andcombinations thereof. Examples of such substituted hydrocarbons arediols, diacids, diamines, hydroxyacids, amino acids and amino alcohols.The substituted hydrocarbons may be α,ω-substituted alkylenes orα,ω-substituted (poly)oxycarbonylalkylenes [i.e. α,ω-substitutedpolyesters]. The skilled person will appreciate that when suchα,ω-substituted alkylenes or α,ω-substituted (poly)oxycarbonylalkylenesare used as the linking group, the monomer—bioactive moiety conjugatesof formula (II) or (IIa), and polymers produced therefrom, willtypically comprise at least two functional groups that may besusceptible to cleavage so as to release the bioactive moiety. In thesecompounds, it is preferable that the functional group closest to thebioactive moiety is as susceptible to, or more susceptible to, cleavagethan the functional group closest to the polymer backbone.

Specific examples of spacer moieties include: —O—; —C(O)—; andoptionally substituted: —OC(O)—C₁₋₁₈alkylene-C(O)—;—C(O)O—C₁₋₁₈alkylene-C(O)—; —NR^(a)C(O)—C₁₋₁₈alkylene-C(O)—;C(O)O—C₁₋₁₈alkylene-O—; —O—C₁₋₁₈alkylene-O—; —O—C₁₋₁₈alkylene-NR^(a)—;—OC(O)—C₁₋₁₈alkylene-NR^(a)—; —C(O)—C₁₋₁₈alkylene-NR^(a)—;—OC(O)—C₁₋₁₈alkylene-O—; —C(O)—C₁₋₁₈alkylene-O—; and—C(O)NR^(a)—C₁₋₁₈alkylene-NR^(a)— where R^(a) is as defined above.

Preferred examples of spacer moieties include: —O—; —C(O)—; and—OC(O)—C₁₋₁₈alkylene-C(O)—, such as —OC(O)—C₂₋₃alkylene-C(O)—.

An example of a monomer-bioactive moiety conjugate of formula (II) thatcomprises a —OC(O)—C₁₋₁₈alkylene-C(O)— spacer moiety (Z) is shown below:

where:

X′, Y′ R and D are as herein defined.

In one embodiment, X′ and Y′ are each hydroxyl.

An example of a monomer-bioactive agent conjugate of formula (IIa) thatcomprises a —OC(O)—C₁₋₁₈alkylene-C(O)— linking group (Z) is shown below:

wherein:

-   -   R represents a linear or branched optionally substituted        hydrocarbon; and    -   D is a releasable bioactive moiety.

The monomer-bioactive moiety conjugate precursor (i.e. the monomer priorto conjugate addition of the bioactive moiety—herein after convenientlyreferred to as the precursor monomer) must of course have a means forchemical attachment to the bioactive moiety or to a spacer moiety. Thetypes of functional groups on the precursor suitable for such attachmentinclude hydroxyl, carboxylate, amino, thiol, phosphate or combinationsthereof. The precursor may be singly of multiply functionalised withbioactive moieties.

As discussed above, the bioactive moiety must correspondingly have ameans for chemical attachment to the precursor monomer or to a spacermoiety. The types of functional groups on the bioactive moiety suitablefor attachment include hydroxyl, carboxylate, amino, thiol, phosphate orcombinations thereof.

Where a spacer moiety is used, as discussed above it must have at leasttwo functional groups for chemical attachment, one to the bioactivemoiety the other to the precursor monomer. Useful spacer moietyprecursors (i.e. the spacer moiety prior to being covalently attached tothe polymer or bioactive moiety) may include functional groups such ashydroxyl, carboxylate, amino, thiol, phosphate or combinations thereof.

The spacer moieties may be derived from precursors that comprise two ormore functional groups which may be the same or different. Examples ofprecursors from which the spacer moieties may be derived that contain asingle type of functional group include dicarboxylic acids (e.g.,malonic acid), diols (e.g., propylene glycol), polyols (e.g., glycerol),dithiols (e.g., 1,3-propanedithiol). Examples of precursors from whichthe spacer moieties may be derived that contain two or more differentfunctional groups include glycolic acid, citric acid, tartaric acid,lactic acid, salicylic acid, lysine, serine, aspartic acid, cysteine,etc. Using such precursors is advantageous when seeking to couple abioactive moiety to a monomer precursor through the same type offunctional group. For example, coupling the carboxylic acid on abioactive moiety to a carboxylic acid on a monomer precursor can beachieved with a diol or polyol spacer. Conversely, coupling a hydroxylon a bioactive moiety to a hydroxyl on a monomer precursor can beachieved with a diarboxylic acid (e.g., malonic acid) spacer.

Use of the spacer moieties can provide facile coupling of the bioactivemoiety to the R group. In particular, spacer moieties may provide theskilled worker with the ability to couple the bioactive moiety at asterically hindered position that could not otherwise be achieved bydirectly coupling the moiety to the R group.

The choice of spacer moieties will determine the spacing of the D fromthe X′ and Y′ groups in the monomers of formula (II). In this respect,the use of spacer moieties can provide a means to distance D from thesegroups. This can facilitate polymerisation of the monomers by reducingsteric crowding around the X′ and Y′ groups.

In forming a monomer of formula (II), prior to conjugation the bioactivemoiety (denoted by D) necessarily comprises compatible functionality soas to promote coupling of the bioactive moiety to the monomer through Z.

Examples of such compatible functionalities in D can include:

-   -   (i) carboxylic acids, sulfates and phosphates (e.g. for reacting        with a spacer precursor moiety comprising a primary amino,        secondary amino or hydroxy group to couple the bioactive moiety        to the monomer through a nitrogen atom or an oxygen atom        containing spacer moiety); and    -   (ii) carboxylic acids, hydroxyls, amines (primary and secondary)        thiols and phosphates (e.g. for reacting with a spacer precursor        moiety comprising a carboxylic acid or acid halide group to        couple the bioactive moiety to monomer through a carbonyl group        containing spacer moiety).

Those skilled in the art will appreciate that the process of preparingthe monomer—bioactive moiety conjugate will typically result inexpulsion of a small molecule such as water or hydrogen halide (e.g.HCl). For example, the formation of an ester bond through reaction of acarboxylic acid group with a hydroxy group liberates a water molecule.

In some embodiments, the bioactive moiety comprises a carboxylic acid,hydroxyl group, thiol group, amine group, or phosphate group, orcombinations thereof for conjugate coupling. When conjugated throughsuch groups, a part or the whole of the Z group can form part of anester, an amide, an anhydride, an azo, an imide, a carbonate, aperoxyester, a thioester, a carbamate, a boronate ester, a sulfate or aphosphate linkage group. The skilled worker will recognise that each ofthese linkage groups comprises a covalent bond that is capable of beingcleaved (for example hydrolytically, enzymatically and/or by a radicalmechanism). Generally, such spacer groups will comprise a covalent bondthat is capable of being cleaved hydrolytically so as to release thebioactive moiety.

Where a given bioactive moiety comprises more than one compatiblefunctional group capable of conjugate coupling, the skilled worker mayroutinely adopt an appropriate protecting group strategy so that thebioactive moiety couples to the monomer in a preselected fashion.Protection group chemistry, and strategy, is well-known in the art in,for example, T. W. Greene and P. G. M. Wuts in “Protective Groups inOrganic Chemistry”, John Wiley and Sons, 1991. For example, where abioactive moiety comprises a primary alcohol and a primary amine, theskilled worker may protect the primary amine prior to coupling thebioactive moiety so that the bioactive moiety couples through an estermoiety rather than an amide moiety. In another example a primary alcoholmay be protected selectively over a secondary alcohol, so that thebioactive moiety may be coupled through an ester moiety derived from thesecondary alcohol. Such protecting groups may or may not be removedfollowing coupling. For example, the protecting group may be an acetylgroup, and the acetylated amine or alcohol may undergo cleavage in vivoto return the unprotected amine or alcohol.

Provided that a suitable conjugate can be formed, there is no particularlimitation on the type of bioactive moiety that may be used inaccordance with the invention. The bioactive moiety may be exemplifiedby 5-alpha-reductase inhibitors, amebicides, aminosalicylates,anaesthetics (general and local), analgesics, angiotensin inhibitors,anorexiants, antacid agents, anti-angiogenic agents, antianginal agents,antiarrhythmic agents, antiarthritic agents, antibiotics, antibacterialagents, antibodies, anticoagulants, anticonvulsants, antidepressants,antiepileptic agents, antifungals, anthelmintics, antihistamines,antihypertensives, antihyperlipidemic agents, antiinfectives,antiinflammatories, antiemetics, antimalarial, antimetabolites,antimigraine, antimitotics, antiparasitic agents, antiparkinson agents,antipsychotics, antiprotozoals, antitussives, antiulcer agents,antivirals, anxiolytics, bronchodilators, decongestants andexpectorants, cancer therapy and related pharmaceuticals, cardiovascularpharmaceuticals, central nervous system pharmaceuticals,benzopidazepines, beta-adrenergic blocking agents, bisphosphonates,calcium channel blockers, carbonic anhydrase inhibitors, chemokinereceptor antagonist, coumarins and indadiones, cox-2 inhibitors,contraceptives, cytotoxics, diuretics, diabetes therapies, growthhormones, fertility pharmaceuticals, hematinics, glucose modifyingagents, growth promoters, H2 antagonists, heparin and heparinantagonists, hormone replacement therapies, hemostatics,immunosuppressants, immunostimulants, inotropic agents, interferons,hormones and analogs, impotence agents, kinase inhibitors, laxatives,leukotriene modifiers, macrolides, mast cell stabilizers, musclerelaxants/stimulants, midrates, neuromuscular blocking agents, obesitytherapeutics, ophthalmic pharmaceuticals, osteoporosis drugs, paintherapeutics (including paracetamol, opiates, nonsteroidalantinflammatory agents, tramadol), peptides and polypeptides, peripheralvasodilators, platelet inhibitors/stimulating agents, prolactininhibitors, protease inhibitors, protein therapeutics, proton pumpinhibitors, radiopharmaceuticals, respiratory pharmaceuticals,sedatives, spermicides, steroids (including androgens, anabolic andadrenal cortical), smoking cessation agents, statins, stimulants andtranquilizers, sulphonamides, thyroid drugs, urinaryacidifiers/alkalinisers, and vasodilators.

The bioactive moiety may include any drug or therapeutically activeagent, including pharmacologically active agents (e.g., receptor bindingagonist or antagonists, cytotoxic agents) and pharmacologically inactiveagents (e.g., antibiotics).

Specific examples of bioactive moieties that can be used in the presentinvention are listed below in categories according to their functionalgroups that may be used in conjugate formation. This list is in no waylimiting the scope of drugs covered in this invention, but given asrepresentative examples. All the amino—(including amide-NH andsulfonamide-NH, carbamate-NH, sulfamate-NH, hydrazone-NH,semicarbazone-NH, thiosemicarbazone-NH, urea-NH, phosphoramide-NH andthe like), carboxyl- and hydroxyl-(including oxime-OH), containing drugsunder various therapeutic categories as listed in Merck Index (13theditions) and other data bases such as prous science's ensemble,integrity, and the like and also all the qualified (i.e., amino-, and/orhydroxyl-, and/or carboxyl-containing) investigational drugs as listedin databases such Merck Index (14th. edition), iddb, ensemble,integrity, and the like, are covered under this invention without anylimitation.

Anti-Inflammatory Drugs:

Amino-containing: Ampiroxicam, Bucolome, Celecoxib, Difenpiramide,Mofebutazone, Nimesulide, Paranyline, Parecoxib, Parsalmide,Piketoprofen, Talniflumate, Tenidap, Terofenamate, and Valdecoxib.

Hydroxyl-containing: 21-Acetoxypregnenolone, Alclometasone,Betamethasone, alfa-Bisabolol, Budesonide, Clobetasone, Cyclosporin,Deflazacort, Dexamethasone, Diflorasone, Desonide, Desoximetasone,Diflorasone, Diflucortolone, Difluprednate, Ditazol, Everolimus,Fluazacort, Fludrocortisone, Flumethasone, Fluocinolone, Fluocinonide,Fluocortin Butyl, Fluocortolone, Fluprednidene Acetate, Glucametacin,Halcinonide, Halobetasol Propionate, Halometasone, Halopredone Acetate,Hydrocortisone, Ibuproxam, Loteprednol Etabonate, Mazipredone,Memetasone, Methylprednisolone, Mometasone Furoate, Oxyphenbutazone,Perisoxal, Pimecrolimus, Prednisolone, Prednisone, Rimexolone,Sirolimus, Triamcinolone and Tacrolimus.

Hydroxyl-, and Amino-containing: Bufexamac, Etofenamate, Fepradinol,Ibuproxam, Isoxicam, Lornoxicam, Meloxicam, Oxametacine, Piroxicam, andTenoxicam.

Carboxyl- and Amino-containing: Aceclofenac, Alminoprofen, Amfenac,3-Amino-4-hydroxybutyric Acid, Carprofen, Diclofenac, Enfenamic Acid,Etodolac, Flufenamic Acid, Meclofenamic Acid, Mefenamic Acid, NiflumicAcid, and Tolfenamic Acid.

Carboxyl-containing: Acemetacin, Acetamidocaproic Acid, Bendazac,Benoxaprofen, Bermoprofen, Bucloxic Acid, Butibufen, Cinmetacin,Clidanac, Clopirac, Felbinac, Fenbufen, Fenclozic Acid, Fenoprofen,Fentiazac, Flunoxaprofen, Flurbiprofen, Ibuprofen, Indomethacin,Isofezolac, Isoxepac, Ketoprofen, Lonazolac, Loxoprofen, MetiazinicAcid, Mofezolac, Naproxen, Oxaprozin, Pirazolac, Pirprofen, Pranoprofen,Protizinic Acid, Sulindac, Suprofen, Suxibuzone, Tiaprofenic Acid,Tolmetin, and Tropesin. Bermoprofen, Bucloxic Acid, Isoxepac,Ketoprofen, Loxoprofen, and Zaltoprofen.

Carboxyl- and Hydroxyl-containing: Balsalazide, Enoxolone, Fendosal,Olsalazine, Oxaceprol, and Ximoprofen.

Amino-, Carboxyl- and Hydroxyl-containing: 3-Amino-4-hydroxybutyricAcid, Mesalamine, and Sulfasalazine.

Analgesic and/or Antipyretic Drugs:

Amino-containing: Aminochlorthenoxazin, Aminopropylon, Anileridine,Antrafenine, Benorylate, Benzpiperylon, p-Bromoacetanilide, Butacetin,Carsalam, Difenamizole, Etersalate, Ethenzamide, Ethoxazene, Flipirtine,Isonixin, Nifenazone, Phenacetin, Phenazopyridine, Phenocoll,Phenopyrazone, Piminodine, Piritramide, Propacetamol, Ramifenazone,Piperylone, Salverine, and Tinoridine.

Hydroxyl-containing: Aluminum bis(acetylsalicylate), Benzylmorphine,Buprenorphine, Butorphanol, Chlorobutanol, Ciramadol, Codeine,Desomorphine, Dihydrocodeine, Dihydromorphine, Dihydroxyaluminumacetylsalicylate, Dimepheptanol, Eptazocine, Ethylmorphine, Eugenol,Hydromorphone, Hydroxypethidine, Levorphanol, Meptazinol, Metazocine,Morphine, Nalbuphine, Oxycodone Pentazocine, Phenazocine, Phenoperidine,Phenylsalicylate, Salicin, Tramadol, and Viminol. Hydromorphone,Ketobemidone, Metopon, Oxycodone, and Oxymorphone.

Carboxyl-containing: Acetylsalicylsalicylic acid, Alclofenac, Aspirin,Benoxaprofen, 5-Bromosalicylic acid acetate, Cinchophen, Diacerein,Dipyrocetyl, Fosfosal, Ibufenac, Indoprofen, and Salicysulfuric acid.Clometacin, Ketorolac, and Zomepirac.

Amino- and Hydroxyl-containing: Acetaminophen, Acetaminosalol, Bucetin,Capsaicine, Dezocine, Floctafenine, Glafenine, Isoladol,p-Lactophenetide, Norlevorphanol, Normorphine, Phenylramidol,Salacetamide, and Salicylamide.

Amino- and Carboxyl-containing: Actarit, Bumadizone, Clonixin, andSalicylamide O-acetic acid.

Carboxyl- and Hydroxyl-containing: Diflunisal, Gentisic acid, andSalsalate.

Antihypertensive Drugs:

Amino-containing: Alfuzosin, Benzylhydrochlorothiazide, Bethanidine,Bopindolol, Budralazine, Bunazosin, Ciclosidomine, Clonidine, Clopamide,Cyclopenthiazide, Debrisoquin, Edeserpidine, Diazoxide, Dihydralazine,Doxazosin, Endralazine, Guanabenz, Guanacline, Guanazodine,Guanethidine, Guanochlor, Guanadrel, Guanfacine, Guanoxan,Hydracarbazine, Hydralazine, Hydroflumethiazide, Indapamide, Indoramin,Irbesartan, Ketanserin, Lofexidine, Mebutamate, Mecamylamine, Methyl4-pridyl ketone thiosemicarbazone, Mibefradil, Minoxidil, Monatepil,Moxonidine, Pheniprazine, Pinacidil, Prazosin, Raubasine, Rescinnamine,Reserpiline, Reserpine, Rilmenidine, Syrosingopine, Tasosartan,Terazosin, Tiamenidine, Todralazine, Tolonidine, Tripamide, andUrapidil.

Hydroxy-containing: Ajmaline, Cicletanine, Levcromakalim, Naftopidil,Phenactropinium chloride, and Protoveratrines.

Carboxyl-containing: Eprosartan, Fosinopril, and Telmisartan, Captopril,and Omapatrilat.

Amino- and Carboxyl-containing: Alacepril, gama-Aminobutyric acid,Benazepril, Candesartan, Carmoxirole, Caronapril, Cilazapril, Delapril,Enalapril, Enalaprilat, Imidapril, Lisinopril, Moexipril, Moveltipril,Perindopril, Quinapril, Ramipril, Saralasin, Spirapril, Temocapril,Trandolapril, and Valsartan.

Amino- and Hydroxyl-containing: Acebutolol, Alprenolol, Amosulalol,Arotinolol, Atenolol, Betaxolol, Bisoprolol, Bosentan, Bucindolol,Bufeniode, Bunitrolol, Bupranolol, Butofilolol, Cadralazine, Celiprolol,Carazolol, Carteolol, Cetamolol, Carvedilol, Epanolol, Indenolol,Nadolol, Dilevalol, Fenoldopam, Guanoxabenz, Labetalol, Losartan,Mepindolol, Metipranolol, Metoprolol, Moprolol, Nebivolol, Olmesartan,Oxprenolol, Penbutolol, Phentolamine, Pildralazine, Pindolol,Propranolol, Rescimetol, Sulfinalol, Talinolol, Tertatolol, Timolol, andTrimazosin.

Amino-, Hydroxyl- and Carboxyl-containing: Methyldopa, and Sampatrilat.

Antibiotics:

All the known amino-, hydroxyl-, and carboxyl-containing antibioticssuch as Amoxicillin, Ampicillin, Olivanic acid, Metronidazole, and thelike as listed in Merck Index. 13.sup.th edition and other drugdatabases integrity, ensemble, iddb, and the like. These antibiotics canbe used in combination with beta-lactamase inhibitor such as clavulanicacid, penicillinic acid sulfone and the like. The following lists ofantibacterial and antifungal agents are given for clarity.

Antibacterial Agents:

Amino-containing: Acedapsone, Acetosulfone sodium, Ambazone,Bacampicillin, Benzylsulfamide, Brodimoprim, Cefcapene pivoxil,Cefpodoxime proxetil, Chloramine-B, Chloramine-T, Capreomycin,Clofazimine, Cyacetacide, Cycloserine, Dapsone, Ethionamide, Furazoliumchloride, N2-Formylsulfisomidine, Furonazide, Isoniazid, Lenampicillin,Linezolide, Mafenide, 4′-(Methylsulfamoyl)sulfanilanilide,Morphazinamide, Nifuradene, Nitrofurantoin, Penamecillin, Penethamatehydriodide, Pexiganan, Pivampicillin, Pivcefalexin, Picloxydine,Protionamide, Pyrazinamide, Solasulfone, Subathizone,4,4′-Sulfinyldianiline, Sulfoxone sodium, 4′-Sulfanilylsulfanilamide,Sulfoniazide, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine,Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine,Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanole, Sulfalene,Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,Sulframethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,Sulfamethylthiazole, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole,Sulfanilamide, p-Sulfanilylbenzylamine, Sulfanilylurea,N-Sulfanilyl-3,4-xylamide, Sulfaperine, Sulfaphenazole, Sulfaproxyline,Sulfapyrazine, Sulfasomizole, Sulfasymazine, Sulfathiazole,Sulfathiourea, Sulfisomidine, Sulfisoxazole, Sultamicillin,Sulfatolamide, Talampicillin, Taurolidine, Tetroxoprim, Thiazosulfone,Thiacetazone, Tiocarlide, and Trimethoprim.

Hydroxyl-containing: Azithromycin, Chloroxylenol, Chlorquinadol,Clindamycin, Clofoctol, Cloxyquin, Diathymosulfone, Doxycycline,Glucosulfone sodium, Nifurpirinol, Nifurtoinol, Nitroxoline, Roxarsone,Roxithromycin, Xanthocillin, and Xibomol. Carbomycin, Clarithromycin,Erythromycin, all erythromycin ester derivatives, Oleandomycin, andTelithromycin.

Carboxyl-containing (including sulfate, phosphate andphosphonate-containing): Amdinocillin, Cinoxacin, Difloxacin,Fosfomycin, and Hydnocarpic acid. Fleroxacin, Flumequine, Miloxacin,Nalidixic acid, Ofloxacin, Oxolinic acid, Pefloxacin, Piromidic acid,Prulifloxacin, Rosoxacin, and Rufloxacin.

Amino- and Carboxyl-containing (including sulfate-, sulfonic acid-,phosphate and phosphonate-containing): Acediasulfone, Amphomycin,Ampicillin, Azidocillin, Azlocillin, Aztreonam, Bacitracin,Balofloxacin, Betamipron, Carbenicillin, Carindacillin, Carumonam,Cefaclor, Cefazedone, Cefazolin, Cefclidin, Cefditoren, Cefepime,Cefetamet, Cefixime, Cefinenoxime, Cefinetazole, Cefodizime, Ceforanide,Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefozopran, Cefpimizole,Cefpirome, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole,Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam,Cephacetrile sodium, Cephalexin, Cephaloglycin, Cephaloridine,Cephalosporin C, Cephalothin, Cephapirin sodium, Cephradine, Cilastatin,Ciproflaxacin, Clinafloxacin, Clometocillin, Cyclacillin, Dicloxacillin,Enoxacin, Epicillin, Fenbenicillin, Floxacillin, Hetacillin, Loracarbef,Metampicillin, Methicillin, Mezlocillin, Nafcillin, Noprysulfamide,Opiniazide, Oxacillin, Penicillin(s), Penimepicycline, Phenethicillin,Phthalylsulfacetamide, Phthalylsulfathiazole, Piperacillin, Propicillin,Quinacillin, Succinylsulfathiazole, Succisulfone, Sulbenicillin,Sulfachrysoidine, Sulfanilic acid, Temocillin, Ticarcillin, andTigemonam. Garenoxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin,Lomefloxacin, Moxifloxacin, Norfloxacin, Pazufloxacin, Pipemidic acid,Sitafloxacin, Sparfloxacin, Tosufloxacin, and Trovafloxacin.

Amino- and Hydroxyl-containing: Amikacin, p-Aminosalicylic acidhydrazide, Arbekacin, Azidamfenicol, Bambermycins,5-Bromosalicylhydroxamic acid, Butirosin, Clindamycin, Clomocycline,Chloramphenicol, Cloxacillin, Colistin, Demeclocycline,Deoxydihydrostreptomycin, Dibekacin, Dihydrostreptomycin, Dirithromycin,Doxycycline, Enviomycin, Ethambutol, Forimicins, Gentamycin,Glyconiazide, N4-beta-D-Glucosylsulfanilamide, Gramicidin(s),Isepamicin, Kanamycin(s), Lincomycin, Meclocycline, Methacycline,Micronomicin, Neomycin, Netilmicin, Novobiocin, Paromomycin, Phenylaminosalicylate, Pipacycline, Polymyxin, Primycin, Ramoplanin,Ribostamycin, Rifabutin, Rifalazil, Rifamide, Rifamycin SV, Rifampin,Rifapentine, Rifaximin, Ristocetin, Salinazid, Sancycline, Sisomicin,Streptolydigin, Streptomycin, Streptonicozid,2-p-Sulfanilylanilinoethanol, Thiamphenicol, Thiostrepton, Tobramycin,Tuberactinomycin, Viomycin, and Virginiamycin. Chlortetracycline,Dalfopristin, Guamecycline, Mikamycin, Minocycline, Oxytetracycline,Pristinamycin, Quinupristin, Rolitetracycline, Spectinomycin, andTrospectomycin.

Hydroxyl- and Carboxyl-containing (including sulfate, phosphate andphosphonate-containing): Fropenem, Nadifloxacin, Biapenem, Fusidic acid,and Merbromin.

Amino-, Hydroxyl-, and Carboxyl-containing (including sulfate, phosphateand phosphonate-containing): p-Aminosalicylic acid, Apicycline,Amoxicillin, Apalcillin, Aspoxicillin, Benzoylpas, Cefadroxil,Cefamandole, Cefatrizine, Cefbuperazone, Cefdinir, Cefminox, Cefonicid,Cefoperazone, Cefoselis, Cefpiramide, Cefprozil, Ertapenem, Flomoxef,Imipenem, Lymecycline, Meropenem, Moxalactam, Negamycin, Panipenem,Ritipenem, Salazosulfadimidine, Sulfaloxic acid,4-Sulfanilamidosalicylic acid, Teicoplanin, Tyrocidine, and Vancomycin.

Antifungal Agents:

Amino-containing: Chlordantoin, Exalamide, Flucytosine, Loflucarban.

Hydroxy-containing: Chlorphenesin, Ciclopirox, Delmostatin, Filipin,Fluconazole, Fungichromin, Pecilocin, Posaconazole, Ravuconazole,Rubijervine, Siccanin, 2,4,6-Tribromo-m-cresol and Voriconazole.

Carboxyl-containing: Undecylenic acid (10-undecenoic acid), andPropionic acid.

Amino- and Carboxyl-containing: Azaserine.

Amino- and Hydroxyl-containing: Salicylanilide, Acrisorcin(9-Aminoacrindine compound with 4-Hexylresorcinol (1:1)), Anidulafungin,Bromosalicylchloranilide, Buclosamide, Caspofungin, Micafungin, andTubercidin.

Amino-, Carboxyl- and Hydroxyl-containing: Natamycin, Amphotericin B,Lucensomycin, and Nystatin.

Antiviral Drugs:

Hydroxy-containing: Edoxudine, Floxuridine, Idoxuridine, Kethoxal,Podophyllotoxin, Sorivudine, Stavudine, Trifluridine, and Zidovudine.

Amino-containing: Amantadine, Amidinomycin, Atevirdine, Capravirine,Delavirdine, Efavirenz, Famciclovir, Imiquimod, Lamivudine, Methisazone,Moroxydine, Nevirapine, Oseltamivir, Rimantadine, Stallimycin,mantadine, and Valacyclovir.

Amino- and Hydroxyl-containing: Abacavir, Acyclovir, Adefovir,Amprenavir, Atazanavir, Cidofovir, Didanosine, Dideoxyadenosine,Emtricitabine, Entecavir, Indinavir, Lamivudine, Lopinavir,5-(methylamino)-2-deoxyuridine (MADU), Nelfinavir, Penciclovir,Resiquimod, Ribavirin, Ritonavir, Saquinavir, Tenofovir, Tipranavir,Valganciclovir, Vidarabine, and Zalcitabine.

Carboxyl- and Hydroxyl-containing: Foscarnet sodium, and Ganciclovir.

Amino-, Carboxyl- and Hydroxyl-containing: Zanamivir.

Antimalarial:

Amino-containing: Chlorguanide, Chloroquine, Chlorproguanil,Cycloguanil, Pamaquine, Plasmocid, Primaquine, Quinocide, andTafenoquine.

Hydroxyl-containing: Artemisinin alcohol, Bebeerines, Cinchonidine,Cinchonine, Dihydroartemisinin, Halofantrine, Lumefantrine, Quinine andYingzhaosu A.

Carboxyl-containing: Arteflene and Artesunate.

Amino-, and Hydroxyl-containing: Amodiaquin, Hydroxychloroquine,Mefloquine, and Pyronaridine.

Antineoplastic Drugs:

Hydroxy-containing: Aclacinomycins, Arzoxifene, Batimastat, Broxuridine,Calusterone, Capecitabine, CC-1065, Chromomycins, Diethylstilbestrol,Docetaxel, Doxifluridine, Droloxifene, Dromostanolone, Enocitabine,Epitiostanol, Estramustine, Etanidazole, Etoposide, Fenretinide,Flavopiridol, Formestane, Fosfestrol, Fulvestrant, Gemcitabine,Irinotecan, Melengestrol, Menogaril, Miltefosine, Mitobronitol,Mitolactol, Mopidamol, Nitracrine, Nogalamycin, NordihydroguaiareticAcid, Olivomycins, Paclitaxel and other known paclitaxel analogs,Plicamycin, Podophyllotoxin, Retinoic acid (including all trans-retiniocacid), Roquinimex, Rubitecan, Seocalcitol, Temoporfin, Teniposide,Tenuazonic Acid, Topotecan, Valrubicin, Vinblastine, Vincristine, andZosuquidar.

Amino-containing (including Amide-NH and Sulphonamide-NH, Carbamate-NH,Sulfamate-NH, and Phosphomide-NH): 9-Aminocamptothecin, AminolevulinicAcid, Amsacrine, Bisantrene, Cactinomyc in, Carboquone, Carmofur,Carmustine, Cyclophosphamide, Dacarbazine, Dactinomycin, Demecolcine,Diaziquone, 6-Diazo-5-oxo-L-norleucine (DON), Edatrexate, Efaproxiral,Eflornithine, Eniluracil, Erlotinib, Fluorouracil, Gefitinib,Gemcitabine, Goserelin, Histamine, Ifosfamide, Imatinib, Improsulfan,Lanreotide, Leuprolide, Liarozole, Lobaplatin, Cisplatin, Carboplatin,Lomustine, Lonafarnib, Mannomustine, Melphalan, Methotrexate, MethylAminolevulinate, Miboplatin, Mitoguazone, Mitoxantrone, Nilutamide,Nimustine, Nolatrexed, Oxaliplatin, Pemetrexed, Phenamet, Piritrexim,Procarbazine, Raltitrexed, Tariquidar, Temozolomide, Thiamiprine,Thioguanine, Tipifamib, Tirapazamine, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP)/3-Aminopyridine-4-methyl-2-carboxaldehydethiosemicarbazone (3-AMP/Triapine/OCX-191/OCX-0191), Trimetrexate,Uracil Mustard, Uredepa ([Bis(1-aziridinyl)phosphinyl]carbamic acidethyl ester, ethyl carbamate and Meturedepa.

Both Hydroxy-& Amino-containing (including Amide-NH and Sulphonamide-NH,Carbamate-NH, Sulfamate-NH, and Phosphomide-NH): Ancitabine,Anthramycin, Azacitidine, Bleomycins, Bropirimine, Buserelin, Carubicin,Chlorozotocin, Cladribine, Cytarabine, Daunorubicin, Decitabine,Defosfamide, Docetaxel, Doxorubicin, Ecteinascidins, Epirubicin,Gemcitabine, Hydroxyurea, Idarubicin, Marimastat, 6-Mercaptopurine,Pentostatin, Peplomycin, Perfosfamide, Pirarubicin, Prinomastat,Puromycin, Ranimustine, Streptonigrin, Streptozocin, Tiazofurin,Troxacitabine, Vindesine and Zorubicin.

Carboxyl-containing: Butyric acid.

Antiglaucoma Agents:

Amino-containing: Acetazolamide, Brimonidine and Pilocarpine.

Amino- and Hydroxyl-containing: Bimatoprost and Timolol.

Hydroxyl-containing: Latanoprost, Bimatoprost and Travoprost.

Benzodiazepine Tranquilizers and Hypnotics:

Diazepam, Triazolam, Alprazolam, and the like.

Antiulcer Agents:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Aldioxa, Benexate HCl, Cimetidine, Ebrotidine, Ecabapide,Esaprazole, Esomeprazole, Famotidine, Irsogladine, Lafutidine,Lansoprazole, Omeprazole, Pantoprazole, Pirenzepine, Polaprezinc,Rabeprazole, Ranitidine, Roxatidine, and Troxipide.

Hydroxyl-containing: Enprostil, Misoprostol, Ornoprostil, Plaunotol,Rioprostil, Trimoprostil, and Oryzanol A.

Carboxyl-containing: Acetoxolone, Carbenoxolone, Rebamipide, andSofalcone.

Amino (or Hydroxyl)- and Carboxyl-containing: Cetraxate, Ecabet,S-Methylmethionine, Rosaprostol, and Rotraxate.

Anticonvulsants:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Acetylpheneturide, Albutoin, N-benzyl-3-chloropropionamide,Carbamazepine, Cinromide, Clonazepam, Decimemide, Dimethadione,Doxenitoin, Ethosuximide, Ethotoin, Felbamate, Fosphenyloin,Lamotrigine, Levetiracetam, Mephenyloin, Mephobarbital, Metharbital,Methetoin, Nitrazepam, Oxcarbazepine, Oxicarbamazepine, Phenacemide,Phenetharbital, Pheneturide, Phenobarbital, Phenylmethylbarbituric Acid,Phenyloin, Phethenylate Sodium, Primidone, Progabide, Remacemide,Rufinamide, Suclofenide, Sulthiame, Talampanel, Tetrantoin, Topiramate,Valpromide, Zonisamide, 5-Methyl-5-(3-phenanthryl)hydantoin, and3-Methyl-5-phenylhydantoin.

Hydroxyl-containing: Ganaxolone.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH): 4-Amino-3-hydroxybutyric Acid, Atrolactamide, andBuramate.

Carboxyl- and Amino-Containing (including Amide NH and Sulphonamide NHand Phosphomide NH): Gabapentin, Pregabalin, and Vigabatrin.

Carboxyl-containing: Tiagabine, and Valproic Acid.

Antiparkinson

Levodopa and Carbidopa.

Antidepressant:

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Amoxapine, Caroxazone, Demexiptiline, Desipramine,Duloxetine, Fluoxetine, Fluvoxamine, Indalpine, IndeloxazineHydrochloride, Iproclozide, Iproniazid, Isocarboxazid,Levophacetoperane, Maprotiline, Metapramine, Milnacipran, Minaprine,Moclobemide, Nialamide, Nomifensine, Nortriptyline, Octamoxin,Oxypertine, Paroxetine, Protriptyline, Reboxetine, Rolipram, Sertraline,Tofenacin, Tranylcypromine, Viloxazine, Benmoxine, and Rolicyprine.

Hydroxyl-containing: Befloxatone, Bupropion, Fenpentadiol, Hypericin,Opipramol, Pyrisuccideanol, Toloxatone, and Venlafaxine.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH): S-Adenosylmethionine, 5-Hydroxytryptophan, andRoxindole.

Carboxyl- and Amino-Containing (including Amide NH and Sulphonamide NHand Phosphomide NH): Amineptine, and Tianeptine.

Antihistaminic

Amino-containing (including Amide NH and Sulphonamide NH and PhosphomideNH, etc.): Antazoline, Astemizole, Clobenzepam, Desloratadine,Epinastine, Metron S, Mizolastine, and Tritoqualine.

Hydroxyl-containing: Terfenadine, and N-HydroxyethylpromethazineChloride.

Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NHand Phosphomide NH, etc.): Cetoxime.

Carboxyl-containing: Acrivastine, Bepotastine, Cetirizine, andLevocabastine.

Carboxyl- and Hydroxyl-containing: Fexofenadine.

Anticancer, Antioxidative, Antiinflammatory, and Cardioprotective Agent:

Trans-Resveratrol [(E)-3,4′,5-trihydroxystilbene).

Antidiabetic:

Metformin, and Nateglinide/Glipizide/Glibenclamide (Glyburide).

Local Anaesthetics

Amino-containing: Benzocaine, Chloroprocaine, Proparacaine, Tetracaine,Cocaine, Propoxycaine, Procaine, Proparacaine, Tetracaine, Articaine,Bupivacaine, Carticaine, Cinchocaine, Etidocaine, Levobupivacaine,Lignocaine, Mepivacaine, Piperocaine, Prilocalne, Ropivacaine,Trimecaine

It should be understood that while the lists of names of variouscategories of drugs have been included above, such lists are presentedin a way of illustration of the structural features of the qualifyingdrugs in this invention and therefore, the number and types of listeddrugs are not necessarily limited thereto. In principal, any amino-,and/or carboxyl, and/or carbonyl-, and/or hydroxyl-containing drug (fromboth known and investigational drugs), irrespective of its therapeuticcategory and their mechanism of action, as listed in drug databases suchas Merck Index, prous science's ensemble, integrity, iddb, and the like,are generally covered within the true spirit and scope of the presentinvention. For clarity, in addition to the above lists of drugs, anyamino-, and/or carboxyl-, and/or carbonyl-, and/or hydroxyl-containingdrug(s) (both known and investigational drugs) from the followingtherapeutic areas are covered without any limitation:

Central Nervous System:

Sedatives, Hypnotics, Antidepressants, Antipsychotics and Antimanics,Analgesics & Antipyretics, Antimigraine agents, Anticonvulsants, Drugsused in parkinsonism and movement disorders, Drug for dementia,Antiemetics, drugs for Vertigo, CNS Stimulants & activators. Quetiapine,Paliperidone (active metabolite of risperidone), Fluphenazine

Eye:

Antiinfective eye preparations, Antiinflammatory and antiallergicpreparations, antiglaucoma drugs and other preparations to cure eyediseases.

Ear, Nose and Oropharynx:

Drugs used aural, nasal and oropharyngeal preparation.

Cardiovascular System:

Antiarrhythemic drugs, Antihypertensives (including alfa/beta-blockers,channel blockers, ACE inhibitors, Angiotensin H receptor antagonists,diuretics, etc.), Antianginals (including nitrates, calcium channelblockers, etc.), Drugs for cardiac failure and shock, Vasodilators,Coagulants, Anticoagulants, Thrombolytics and antiplatelet drugs.

Respiratory System:

Respiratory stimulants, Antitussives, Expectorants, Mucolytics andDecongestants, Antihistamine agents, and antiasthmatics.

Gastro Intestinal Tract:

Antiulcer and Antisecretory drugs (including H.sub.2 receptorantagonists, Proton Pump Inhibitors, Prostaglandin analogues, etc.),Antacids, Antispasmodics and drugs modifying intestinal motility,Antidiarrhoeals (including antimotility and antimicrobial drugs) anddrugs acting on gall bladder.

Genito Urinary System:

Urinary antiinfectives, Diuretics, Urinary analgesics & antispasmodics,Antiinfective drugs acting on urethra and vagina, drugs acting onuterus, Drugs for prostatic hypertrophy (including alfa blockers andantiandrogens), Drugs for erectile dysfunction, and Spermicidal &nonhormonal contraceptives.

Skin:

Keratolytics, topical antiinfectives, topical antifungals, topicalparasiticidals, topical steroids, topical drugs for acne vulgaris, drugsfor psoriasis, pigmentation disorders, and Antiseborrhoeics.

Musculo-Skeletal Disorders:

Non Steroidal Anti Inflammatory Drugs (NSAIDs) including COX-2inhibitors, Antiarthritic agents, Immunosuppressants, Topicalanalgesics, Muscle relaxants and Neuromuscular Drugs.

Infections and Infestations:

Penicillin antibiotics, Cephalosporin antibiotics, Quinolone &Fluoroquinolone antibiotics, Macrolide antibiotics, Chloramphenicol,Tetracycline antibiotics, Sulfonamides, Antianaerobics such asMetronidazole, Antitubercular drugs, Antileprosy drugs, Antifungals,Antiprotozoals, Anthelminthics & Antiinfestive Drugs, Antimalarials andAntivirals.

Endocrine System:

Anabolic and androgenic steroids, Corticosteroids, Oestrogens,Progestogens and Hormonal contraceptives, Fertility Agents, Trophichormones and related drugs, Thyroid and antithyroid drugs, Antidiabeticsand hyperglycaemics.

Metabolism:

Hypolipidaemic drugs (including fibric acid derivatives, statins [(i.e.,HMG CoA reductase inhibitors), nicotinic acid group, etc.], Drugs usedfor Gout and Drugs affecting bone metabolism (includingbisphosphonates).

Neoplastic Disorders:

Anticancer drugs such as alkylating agents, cytotoxic antibiotics,antimetabolites such as cytarbine, Fludarbine, 5-Fluorouracil,Mercaptopurine, Thioguanine, etc., Vinca alkaloids and Etoposide,Taxanes, Topoisomerase 1 inhibitors, Cytotoxic immunosuppressants,Immunostmulants, Cytoprotectives such as Amifostine, Oestrogens,Progestogens, hormon antagonists and other antineoplastic drugs.

Allergy and Immunology:

Antiallurgics such as non-sedative antihistamins (e.g., Cetirizine,Desloratadine, Terfenadine, Fexofenadine, etc.), sedative histamines andhistamine receptor blockers.

Anaesthetics & Surgicals:

Local anaesthetics, intravenous anaesthetics, inhalation anaestheticsand muscle relaxants.

In addition to the above list of drugs, the present invention alsocovers newer drugs with the above mentioned active functional groups aslisted in the Merck index (14.th edition) and other drug databases suchas Prous Science's ensemble, integrity and the investigational drugs aslisted in databases such as iddb, ensemble, integrity, and the likewithout any limitation.

Preferred bioactive agents include the fluoroquinolone antibiotics,local anesthetics and valproic acid. Preferred fluoroquinoloneantibiotics include; alatrofloxacin, balofloxacin, ciprofloxacin,clinafloxacin, danofoxacin, delafloxacin, dextrofloxacin, difloxacin,enoxacin, enrofloxacin, garenoxacin, gatifloxacin, gemifloxacin,grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin,nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin,sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, tosulfloxacinand trovafloxacin. Still further preferred are: danafloxacin,detrofloxacin, difloxacin, enrofloxacin, marbofloxacin, moxifloxacin,levofloxacin, ofloxacin, pefloxacin. Still further preferred islevofloxacin and moxifloxacin. Most preferred is levofloxacin andmoxifloxacin. The preferred local anaesthetics are benzocaine andprocaine, most preferred is benzocaine.

Preferred bioactive moieties that can be utilised in the presentinvention are those containing one or more functional groups such ascarboxylate, hydroxyl, amino, thiol, phosphate or sulphate.

Examples of preferred bioactive moieties that can be utilised in thepresent invention are levofloxacin and valproic acid.

In accordance with the invention the bioactive moieties are capable ofbeing released at a rate equal to or faster than the rate ofbiodegradation of the polymer backbone. By providing the biodegradablepolymer with such properties, structural integrity of the polymerbackbone (and hence the physical form (e.g. shape and size etc) in whichthe polymer is provided) can be maintained while the drug is beingreleased.

By the bioactive moieties being “released at a rate equal to or fasterthan the rate of biodegradation of the polymer backbone” is meant thatthe biodegradable polymer is constructed such that under givenphysiological conditions or in a given biological environment themeasurable concentration of the released bioactive moiety in itsbiologically active form is equal to or greater than the measurableconcentration of the corresponding monomer-bioactive moiety conjugatefrom which the polymer is derived (e.g. formula (II)). Suchconcentration measurement may be readily conducted by those skilled inthe art, for example by using HPLC or GC analytical techniques.

In one embodiment, the bioactive moieties are capable of being releasedat a rate faster than the rate of biodegradation of the polymerbackbone. In that case, the biodegradable polymer is constructed suchthat under given physiological conditions or in a given biologicalenvironment the measurable concentration of the released bioactivemoiety in its biologically active form is greater than the measurableconcentration of the corresponding monomer-bioactive moiety conjugatefrom which the polymer is derived (e.g. formula (II)).

In one a further embodiment, the measurable concentration of thereleased bioactive moiety in its biologically active form is at least5%, at least 10%, at least 20%, at least 40%, at least 50%, at 1×, atleast 2× at least 5× greater than the measurable concentration of thecorresponding monomer-bioactive agent conjugate from which the polymeris derived (e.g. formula (II)).

In connection with providing the biodegradable polymers with anappropriate structure to promote a desired rate of release of thebioactive moiety, those skilled in the art will appreciate, for example,that hydrolysis of an ester moiety will typically occur more readilythan that of an amide or carbamate moiety. Thus to promote a rate ofrelease of the bioactive moiety from the polymer backbone that is, forexample, faster than the rate of biodegradation of the polymer backbone,one might construct the conjugate such that the polymer backbonecomprises only amide and/or carbamate biodegradable moieties and thebioactive moiety is covalently coupled to the backbone via an estermoiety.

Those skilled in the art will also appreciate that factors such assteric crowing and electronic effects around a given biodegradablemoiety can alter its propensity to undergo hydrolytic cleavage. Both thepolymer backbone and the pendant bioactive moiety can be a source ofsuch effects. For example, a biodegradable moiety having a non hydrogensubstituent (e.g. alkyl, aryl, alkylaryl, carbocyclyl) located α and/orβ to it will typically be less susceptible to hydrolytic cleavagerelative to the same moiety having hydrogen substituents located αand/or β to it. Accordingly, steric crowing around a given biodegradablemoiety can be used to influence the rate of release of the bioactivemoiety and/or the rate bio of the polymer backbone.

The skilled artisan would be capable of selecting the appropriate spacerbased on an evaluation of steric constraints, phase chemistry andsurface chemistry. For example, larger bioactive moieties can beadvantageously spaced from the monomer by the choice of a longer spacer.

The skilled artisan would also be capable of selecting the appropriatelinkage chemistry in the synthesis of the biodegradable polymer so thatthe rate of bioactive moiety release was equal to or faster than therate of polymer degradation.

Generally, the rate of hydrolytic cleavage will be in the order:anhydride moiety, ester moiety (including carboxylic acid esters,sulphate esters and phosphate esters)>carbamate>amide.

By tailoring at least the rate at which the bioactive moiety is releasedfrom the polymer backbone, the polymer-bioactive moiety conjugates ofthe invention can advantageously function as a sustained bioactivemoiety delivery system.

At the very least the bioactive moiety must be releasable from thepolymer conjugate per se. However, the polymer may also biodegrade invivo or in vitro to a degree such that the polymer backbone fragments,with the moiety remaining tethered to such a fragment(s). In that case,the moiety will nevertheless still be capable of being released orcleaved from the fragment. Having said this, the bioactive moieties muststill be released at a rate equal to or faster than the rate ofbiodegradation of the polymer backbone as herein defined.

In one embodiment, the bioactive moiety is releasable where the polymerbackbone undergoes substantially no biodegradation during the releasetime frame.

A consequence of having a higher rate of bioactive moiety release isthat it avoids the situation of statistical hydrolysis of a long chainpolymer (e.g., polyanhydride) wherein there is the possibility toproduce oligomers of the bioactive moieties in fragments that mayconsequently be eluted from the body as the oligomer before it can bereleased as the active component.

As used herein, the term “constituent monomer” refers to the residue ofthat monomer as it appears in the polymer backbone.

The biodegradable polymers of the present invention may have a structureas represented in FIG. 9. The bioactive moiety, will be attached to thepolymer via a labile linkage that allows release of the bioactive moietyafter administration. Furthermore, the polymer backbone will alsoinclude biodegradable moieties that allow degradation of the polymerafter administration.

The biodegradable polymer will be designed such that release of thebioactive moiety occurs at a rate that is faster than or equal to therate of degradation of the polymer.

Thus, with reference to FIG. 9 the rate of breakdown of the linkages L2is faster than or equal to, preferably faster than, the rate ofbreakdown of the linkages L1. The labile linkage L1 may be characterisedby a covalent bond between the bioactive moiety and the polymerbackbone. Alternatively, the labile linkage may be characterised by thepresence of a spacer moiety between the bioactive moiety and the polymerbackbone.

The linkage within the polymer backbone L2 may be characterised by thepresence of a covalent bond between backbone fragments containing one ormore monomers and/or by a spacer moiety between backbone fragmentscontaining two or more monomers. Polymer backbones containing sidechains may be further characterised by labile linkages within the sidechains.

It will be appreciated that such labile linkages are those through whichthe bioactive moiety is released and the polymer backbone biodegrades.The labile linkages or linkers may therefore also be referred to asbiodegradable moieties.

Providing the bioactive moiety with a different rate of release relativeto the rate of biodegradation of the polymer backbone allows for therelease of substantially all the bioactive moiety prior to the onset ofsignificant polymer backbone degradation.

The biodegradable polymers of the present invention can accommodate highbioactive moiety loadings, minimising the amount of material required todeliver a dose of bioactive moiety. Bioactive moiety loadings of atleast 10% by weight, preferably at least 20% by weight, more preferablyat least 30% by weight relative to the total weight of the biodegradablepolymer may be achieved.

The bioactive moiety loading may also be expressed in terms of its mol %relative to the total number of moles of monomer that form the polymer.Generally, the polymer-bioactive moiety conjugate will comprise at least10, at least 25, at least 35, at least 45 or up to 50 mol % of bioactivemoiety, relative to the total number of moles of monomer that form thepolymer.

In some embodiments, the polymer-bioactive moiety conjugate willcomprise up to 60, up to 70, up to 80, up to 90 and even up to 100 mol %of conjugated bioactive moiety, relative to the total number of moles ofmonomer that form the polymer. However, in that case, it will beappreciated that the amount of conjugated bioactive moiety greater than50 mol % will necessarily be derived from moieties other than the—X—R(ZD)-Y— type moieties shown in general formula (I). For example, theother monomers which a polymerised with the monomer-bioactive moietyconjugate of the invention (formula (II)) may also comprise conjugatedbioactive moiety.

The biodegradable polymer may contain more than one type of bioactivemoiety as illustrated in FIG. 10.

The biodegradable polymer may contain more than one type of linker orbiodegradable moieties as illustrated in FIG. 11.

As discussed above, varying the lability of linker moieties providescontrol over the release profile of the bioactive moieties. More thanone type of linker moiety can be used combined with more than one typeof bioactive moiety so as to provide a method of sequential controlledrelease of multiple bioactive moieties.

In the context of multiple bioactive moieties, the biodegradablepolymers of the present invention offer the advantage of being able tocontrol a) the relative proportions of the bioactive moieties, b) theirrelative positions as attached to the polymer backbone and c) theirdegree of dispersability (e.g. they may be linked to only certainsegments in the polymer).

The rate of breakdown of the labile linkages L2 may be influenced byexternal stimuli so as to externally modulate the release of thebioactive moiety.

The biodegradable polymer can be homogeneous or heterogeneous withrespect to the bioactive moiety(ies) used.

Preferably the biodegradable polymer is designed such that the bioactivemoieties are released unencumbered by excess molecular fragments. Inother words, the bioactive moieties are released such that they do notcomprise a residue derived from the polymer backbone or spacer moiety.By this it is meant that the bioactive moieties are released in theirsubstantially original form (i.e. before being conjugated) and areessentially free from, for example, fragments of oligomer or polymerderived from the polymer backbone. This is highly desirable in avoidingsituations in which a loss of bioactive moiety efficiency occurs throughloss of pharmacological effect through poor transport of, for example,sterically demanding bioactive/oligomer moieties through physiologicalbarriers may occur, resulting in elution of the active bioactive moietyaway from the target site.

The biodegradable polymers of the present invention employ polymerbackbones (as illustrated by A and B in formula (I)) which is preferablyselected from or comprises polyurethane optionally comprising one ormore chain extenders (e.g. polyester), polyanhydride, polycarbonate,polyurea, polyamide, polyimide and polyester (eg PLGA(poly(lactic-co-glycolic acid)), PLA (polylactic acid), PGA(polyglycolic acid), PHB (polyhydroxybutyrate), PCL (polycaprolactone);and copolymers thereof. More preferably the polymer backbones areselected from or comprise: polyurethanes, polyesters, polyamides andcopolymers thereof. Suitable copolymers include poly(urethane-ester) andpoly(ester-urethane).

Provided that the polymer backbone is biodegradable, it may also includechain extenders, star compounds and dendrimers to introduce branchingand spacing between segments within the polymer. The polymer backbonemay be linear, substantially linear, branched, hyperbranched, stars, ablock polymer or co-polymer. Co-polymers may be advantageous in allowingincorporation of more that one bioactive moiety with known relativepositions in the final polymer.

It may also be desirable for the biodegradable polymers to besubstantially amorphous and thus contain a low amount of crystallinesegments. Such polymers can provide a more predictable rate of bioactivemoiety release as well as assisting with the production of materialsthat are more flexible which can assist with producing coatings as wellas assisting with the rate of polymer degradation.

Additional variables such as the choice of co-monomers and the means toproduce the polymers can also assist with the production of highlyamorphous and/or flexible polymers. For example, using monomers such ascaprolactone or polyester polyols such as polycaprolactone diol candecrease the crystallinity and increase the flexibility of the resultingpolymer.

For the polyurethanes it may be important to limit the content of hardsegment (use conventional definition of hard segment—chainextenders+diisocyanates). One example of a typical class of chainextender are low molecular weight diols. Examples of such chainextenders include ethylene glycol, propane diol, propylene glycol,butane diol etc. Apart from the potential toxicity of such chainextenders, limiting the hard segments in the polyurethanes also providesa reason to reduce the low molecular weight diol content as describedabove.

The polymer backbone of the biodegradable polymers of the presentinvention have a molecular weight of about 250 Daltons to about 2 MMDaltons, preferably from 500 Daltons to 500,000 Daltons.

In one embodiment, the biodegradable polymer in accordance with theinvention comprises as part of its polymer backbone a plurality ofmoieties of general formula (I):

A and B, which may be the same or different, represent the remainder ofthe biodegradable polymer backbone. As per the discussion above inrespect of the polymer backbone, A and B may be selected from orcomprises polyurethane optionally comprising one or more chain extenders(e.g. polyester), polyanhydride, polycarbonate, polyurea, polyamide,polyimide and polyester (eg PLGA (poly(lactic-co-glycolic acid)), PLA(polylactic acid), PGA (polyglycolic acid), PHB (polyhydroxybutyrate),PCL (polycaprolactone); and copolymers thereof. In some embodiments, Aand B are selected from or comprise: polyanhydrides; polyurethanes;polyesters; polyamides and copolymers thereof. In some embodiments, Aand B are selected from or comprise a copolymer of polyurethane andpolyester. A and/or B will also comprise one or more bioactive moietiescovalently coupled to the polymer backbone.

In some embodiments, the polymer-bioactive moiety conjugate inaccordance with the invention comprises as part of its polymer backbonea plurality of moieties of general formula (Id):

A and B, which may be the same or different, represent the remainder ofthe biodegradable polymer backbone, wherein A and B are selected from orcomprise a copolymer of polyurethane and polyester. Examples ofpolyesters include PLGA (poly(lactic-co-glycolic acid)), PLA (polylacticacid), PGA (polyglycolic acid), PHB (polyhydroxybutyrate) and PCL(polycaprolactone). In some embodiments, the polyurethanes optionallycomprise one or more chain extenders (e.g. polyester). A and/or B willalso generally comprise one or more bioactive moieties covalently bondedto the polymer backbone.

Depending upon the intended application, A and B may be selected fortheir biocompatible and/or their biodegradable properties. Those skilledin the art can readily select polymers to provide for such properties.

As used herein, “biocompatible polymer” refers to a polymer that both inits intact, that is, as synthesized, state and in its decomposed state(i.e. its degradation products), is compatible with living tissue inthat it is not, or at least is minimally, toxic to living tissue; doesnot, or at least minimally and reparably does, injure living tissue;and/or does not, or at least minimally and/or controllably does, causean immunological reaction in living tissue.

The moiety “R” present in formulae (I), (Ia), (Ib), (Ic), (Id), (II),(IIa) and (VI) represent a linear or branched optionally substitutedhydrocarbon. In some embodiments the hydrocarbon may comprise between 1and 12 carbon atoms, for example between 1 and 6 carbon atoms or 2 or 3carbon atoms. The hydrocarbon may be partially or completely saturatedor unsaturated (including moieties that are aromatic). Specific examplesof R include a moiety having one of the following structures:

A bioactive moiety can be conjugated to all monomers that form thebiodegradable polymer, or only to monomers of a particular character(e.g., polyalcohols) or proportions of monomers.

Monomers conjugated with one bioactive moiety may be polymerised withmonomers conjugated with another different bioactive moiety.

In one embodiment, a monomer-bioactive moiety conjugate that may be usedin preparing the biodegradable polymers has general formula (II):

where, X′, Y′, R, Z and D are as herein defined.

In some embodiments, the monomer-bioactive moiety conjugate has generalformula (IIa):

where, R, Z and D are as herein defined.

In some embodiments, the monomer-bioactive moiety conjugate may have amore specific structure of formula (III), (IV), (V) or (Va):

where D, X′ and Y′ are as herein defined, and p is between 1 and 18.

In some embodiments, in formulae (III), (IV), (V) and (Va), X′ and Y′are each hydroxyl.

Monomers that are polymerised with the monomer-bioactive moietyconjugate to form the biodegradable polymers of the invention will notonly comprise compatible chemical functionality to react with themonomer-bioactive moiety conjugate but that reaction will of course giverise to a biodegradable moiety.

The expression “compatible chemical functionality” refers to chemicalfunctionality that is capable of undergoing reaction with themonomer-bioactive moiety conjugate to form the polymer. For example, themonomers of formula (II) comprise at least two terminal reactivefunctional groups X′ and Y′. These functional groups will react withcompatible functional groups of one or more monomers to form the polymerand give rise to a biodegradable moiety. Thus, where both X′ and Y′ arehydroxyl groups, those skilled in the art will appreciate that they willreact with a variety of functional groups such as: isocyanatefunctionality to form carbamate or urethane linkages; carboxylic acidfunctionality to produce ester linkages; carboxylic acid halidefunctionality to produce ester linkages; ester functionality to producetrans-esterified ester linkages; and anhydride functionality (includingcyclic anhydride groups) to produce ester linkages. The expression“compatible chemical functionality” therefore refers to functionality orgroups such as isocyanate, carboxylic acid, carboxylic acid halide,ester and anhydride (including cyclic anhydride groups) groups.

In some embodiments of a monomer-bioactive moiety conjugate of formula(II), X′ and Y′ are each hydroxyl groups. The hydroxyl groups arecapable of undergoing polymerisation with at least one monomer havingcompatible chemical functionality, and react with the compatiblechemical functionality to afford a biodegradable moiety. In someembodiments, the polymerisation of the monomer of formula (II) with atleast one monomer having compatible chemical functionality affords abiodegradable moiety selected from an ester and urethane (carbamate)moiety.

Accordingly, where both X′ and Y′ are hydroxyl groups, the expression“at least one other monomer comprising compatible chemicalfunctionality” used herein typically refers to monomers comprising oneor more compatible chemical functional groups selected from isocyanate,carboxylic acid, carboxylic acid halide, ester, anhydride (includingcyclic anhydride groups) groups and combinations thereof. Thus in someembodiments, the monomer-bioactive moiety conjugate of formula (II)where X′ and Y′ are each hydroxyl groups can polymerise with at leastone other monomer comprising one or more compatible chemical functionalgroups, where the one or more compatible chemical functional groups areselected from isocyanate, carboxylic acid, carboxylic acid halide,ester, anhydride (including cyclic anhydride groups) groups andcombinations thereof. Preferably, the at least one other monomercomprises a plurality of compatible chemical functional groups. Examplesof such monomers are polyisocyanates and polyacids. Typically themonomers will be a diisocyanate or a diacid.

In some embodiments the at least one other monomer may contain one groupof compatible chemical functionality (as defined herein) in addition toone group such as an amino, thio or hydroxy group which is not, ofitself, compatible for undergoing polymerisation with a monomer offormula (II) where both X′ and Y′ are hydroxyl groups. Examples of suchmonomers are hydroxy-acids and amino acids. In the case of ahydroxy-acid, the carboxylic acid is capable of reacting with a hydroxygroup of the monomer of formula (II) to produce a hydroxy-terminatedcompound.

Likewise in the case of an amino acid, the carboxylic acid is capable ofreacting with the monomer of formula (II) where both X′ and Y′ arehydroxyl groups to produce an amino-terminated compound. Likewise in thecase of a thio acid, the carboxylic acid is capable of reacting with themonomer of formula (II) where both X′ and Y′ are hydroxyl groups toproduce a thio-terminated compound. These hydroxy/amino/thio terminatedcompounds may subsequently undergo reaction with another monomer bearinga carboxylic acid, isocyanate group, etc. so that the polymer backbonemay comprise one or more ester, amide, thioester, urea, urethane,thiocarbamate functional groups.

For example, polymerisation of formula (II) where both X′ and Y′ arehydroxyl groups with a diisocyanate produces a polyurethane. Such apolyurethane will typically comprise 50 mol % diol residue and 50 mol %diisocyanate residue. Where each diol monomer of formula (II) comprisesone bioactive moiety, the “loading” of the bioactive moiety in thepolymer-bioactive moiety conjugate may be designated as 50%.

The polymerisation formula (II) where both X′ and Y′ are hydroxyl groupswith a diacid produces a polyester. Such a polyester will typicallycomprise 50 mol % diol residue and 50 mol % diacid residue. Where eachdiol monomer of formula (II) comprises one bioactive moiety, the“loading” of the bioactive moiety in the polymer-bioactive moietyconjugate is designated herein as 50 mol %, relative to the monomersthat form the polymer.

Those skilled in the art will also recognise that polymerisation offormula (II) where both X′ and Y′ are hydroxyl groups with apolyisocyanate, polyacid or polyester may also take place in thepresence of one or more other types of polyols (e.g. polyester polyols).In some embodiments, the conjugate of formula (II) where both X′ and Y′are hydroxyl groups is polymerised with a polyisocyanate and at leastone other monomer selected from the group consisting of a polyacid, apolyester and a polyester polyol. The structures of the one or moreother types of polyols may or may not comprise one or more bioactivemoieties. An example of this second type of polyol is 1,6-hexanediol.The polymer-bioactive moiety conjugate so-formed may or may not have abioactive moiety loading of less than 50 mol %. For example when formula(II) (where both X′ and Y′ are hydroxyl groups) is polymerised in thepresence of an equimolar amount of 1,6-hexanediol and 2 molarequivalents of diisocyanate, the polyurethane so-formed will typicallycomprise the residues of the three components in the ratio of 1:1:2.Such conjugates are contemplated by the present invention. Such polymersystems may provide a useful means of modifying the physical propertiesof the polymer conjugates.

Similar comments also apply where X′ and/or Y′ represent differentfunctional groups (i.e. other than both being hydroxyl groups). Forexample, X′ and Y′ may each be independently selected from hydroxyl,amine, carboxylic acid, isocyanate, and carboxylic acid halide.

In some embodiments, the present invention provides a monomer-bioactivemoiety conjugate of formula (II) where X′ and Y′ are each hydroxyl andthe bioactive moiety (D) is selected from fluorquinolone antibiotics.Preferred fluorquinolone antibiotics are levofloxacin and moxifloxacin.

In one aspect, the present invention also provides a biodegradablepolymer of formula (I) obtainable by polymerising a monomer-bioactivemoiety conjugate of formula (II):

where:

-   -   X′ and Y′ are each hydroxyl;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a spacer moiety; and    -   D is a releasable bioactive moiety;        with a polyisocyanate and at least one selected from the group        consisting of a polyacid, a polyester, and a polyester polyol.

In one embodiment, the biodegradable polymer of formula (I) isobtainable by polymerising a monomer-bioactive moiety conjugate offormula (II), where X′ and Y′ are each hydroxyl, with a polyisocyanateand a polyester polyol.

Suitable polyisocyanates may be selected from the group consisting ofm-phenylene diisocyanate, p-phenylene diisocyanate, 2,4-toluenediisocyanate, 2,6-toluene diisocyanate, 1,6-hexamethylene diisocyanate,1,4-hexamethylene diisocyanate, 1,3-cyclohexane diisocyanate,1,4-cyclohexane diisocyanate, hexahydro-toluene diisocyanate and itsisomers, isophorone diisocyanate, dicyclo-hexylmethane diisocyanates,1,5-napthylene diisocyanate, 4,4′-diphenylmethane diisocyanate,2,4′diphenylmethane diisocyanate, 4,4′-biphenylene diisocyanate,3,3′-dimethoxy-4,4′-biphenylene diisocyanate,3,3′-dimethyl-diphenylpropane-4,4′-diisocyanate, 2,4,6-toluenetriisocyanate, 4,4′-dimethyl-diphenylmethane-2,2′,5,5′-tetraisocyanate,polymethylene polyphenhyl polyisocyanates and alkyl esters of lysinediisocyanate (preferably ethyl ester of lysine diisocyanate) andcombinations thereof. Preferred polyisocyanates include1,6-hexamethylene diisocyanate and alkyl esters of lysine diisocyanate(preferably ethyl ester of lysine diisocyanate).

Suitable polyester polyols may be selected from the group consisting ofpolycaprolactone diol (PCLD), poly(DL lactide) (DLLA) and poly(lacticacid-co-glycolic acid) (PLGA), and combinations thereof.

Suitable polyacids may be selected from the group consisting of oxalicacid, fumaric acid, maleic acid, succinic acid, glutaric acid, adipicacid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalicacid, dodecanediacid, isophthalic acid, terephthalic acid,dodecylsuccinic acid, napthalene-2,6-dicarboxylic acid,naphthalene-2,7-dicarboxylic acid, cyclohexane dicarboxylic acid,itaconic acid, malonic acid, and mesaconic acid. Preferred polyacidsinclude maleic acid and succinic acid.

Those skilled in the art will be able to selected both X′ and Y′ forreaction with one more monomers having compatible chemical functionalityto afford the biodegradable polymers according to the invention. WhereX′ is a compatible chemical functionality with Y′ (e.g. hydroxyl andcarboxylic acid), those skilled in the art will also appreciate that themonomer-bioactive moiety conjugate may be polymerised with itself (e.g.where the monomer-bioactive moiety conjugate is a hydroxy-acid).

The invention also provides a process for preparing a monomer-bioactivemoiety conjugate of formula (IIa):

wherein:

-   -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a linking group; and    -   D is a releasable bioactive moiety,        said process comprising covalently coupling a linking precursor        group Z′ in a compound of formula (VI):

-   -   wherein:    -   P¹ and P² are each independently H, a protecting group, or P¹        and P² together fond    -   a protecting group; and    -   R is as defined above,        with a group selected from D or D-Z″,    -   wherein:    -   D is a bioactive moiety in protected or unprotected form or        prodrug thereof; and    -   Z″ is a linking precursor group,        wherein the coupling of Z′ with D, or the coupling of Z′ with Z″        in the group D-Z″, forms the

moiety in the conjugate of formula (IIa),and where P¹ and/or P² are protecting groups said process furthercomprises the step of removing the protecting group or groups.

Z′ and Z″ (when present) are each linking precursor groups which affordthe linking group Z in the monomer-bioactive moiety conjugate of formula(IIa).

In some embodiments, Z′ is a moiety comprising a functional group suchas a carboxylic acid, acid halide, primary amino, secondary amino,hydroxy group, thiol group, phosphate group or sulphate group thatcouples to D or couples to Z″ in the group D-Z″.

In some embodiments, Z″ is a moiety comprising a functional group suchas a carboxylic acid, acid halide, primary amino, secondary amino,hydroxy group, thiol group, phosphate group or sulphate group thatcouples to Z′.

For example, the compound of formula (VI) may be derived from a compoundof formula (VII):

wherein Z′ and R are as defined above.

To promote reaction between D or D-Z″ and the Z′ moiety in generalformula (VI), those skilled in the art will appreciate that the relevantcoupling functional group on the bioactive agent may be suitablymodified. For example, where Z′ in formula (VI) comprises a hydroxygroup, ester formation through reaction of this hydroxy group with acarboxylic acid group in D or a carboxylic acid group on Z″ in D-Z″ canin some cases prove difficult. Under these circumstances, esterformation may be facilitated by first converting the carboxylic acidgroup in D or D-Z″ into an acid halide (e.g. acid chloride) group andthen reacting the acid halide group with the hydroxy group. Couplingagents such as those mentioned in Tetrahedron Volume 60, Issue 11, 8Mar. 2004, pages 2447-2467, could also be employed. Exemplary couplingagents include those listed below in Table 1.

TABLE 1 Coupling agents for promoting reaction between carboxylic acid,acid halide and hydroxy groups. Acronym Chemical name DCCN,N′-dicyclohexylcarbodiimide DIEA(DIPEA) diisopropylethylamine EDC1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride HATUO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HBTUO-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateHOBt 1-hydroxybenzotriazole

The compound of formula (VI), where Z′ comprises a hydroxyl group, maybe derived from a compound of formula (VII) through alcohol groupprotection. The compound of formula (VI), where Z′ comprises a primaryor secondary amino group, may be derived from a compound of formula(VII) through amino group protection. In some cases, the compound offormula (VI), where Z′ comprises a carboxylic acid group, may be derivedfrom a compound of formula (VII) using a protection group strategy. Theskilled worker will recognise that the compound of formula (VI), whereZ′ comprises an acid halide, may be derived from the correspondingcompound where Z′ comprises a carboxylic acid.

Where the bioactive agent has more than one functional group that can beused to covalently couple it to a compound of formula (VI), thoseskilled in the art will be able to select appropriate reactionconditions, reagents and/or protecting groups to promote the desiredcoupling reaction.

Techniques, equipment and reagents well known in the art canadvantageously be used to prepare the monomer-bioactive agent conjugatesin accordance with the invention.

Examples of general strategies for synthesising monomer-bioactive moietyconjugates of formula (IIIa), which employ protecting group strategies,are represented in Scheme 1 below (where D is a releasable bioactiveagent; and D′ is that part of the releasable bioactive moiety other thanthe hydroxyl, amine, carboxylic acid, etc):

The R group may be substituted with one or more groups comprising areleasable bioactive agent (D), as shown in the following structurederived from pentaerythritol:

Where there is more than one bioactive moiety within themonomer-bioactive moiety conjugate (or polymer-bioactive moietyconjugate) of the invention, each bioactive moiety may be the same ordifferent, but typically each bioactive moiety will be the same.

It will be appreciated that in the conjugates shown in Scheme 1, each ofthe linking groups is either a —O— or —C(O)— group. The Scheme will ofcourse be equally applicable for other linking groups (Z) hereindescribed.

Examples of general strategies for synthesising monomer-bioactive moietyconjugates of formula (IIa), which employ protecting group strategiesand use diacid-based linking groups, are represented in Scheme 2 below(where p is an integer from eg 1 to 18, D is a releasable bioactivemoiety; and D′ is that part of the releasable bioactive moiety otherthan the hydroxyl, amine, carboxylic acid, etc):

With reference to the aspect of the present invention that provides aprocess for the preparation of a monomer-bioactive agent conjugate offormula (IIa), Scheme 2 provides strategies for coupling compounds offormula (VI) to D and D-Z″. In particular, in the synthesis of thecompound of formula (IIa) denoted by:

the Z group of the conjugate of formula (Ha) may be denoted by:

This Z group is formed through either:

i) the reaction of Z′ as

in a compound of formula (VI) with D as D′-OH; orii) the reaction of Z′ as

in a compound of formula (VI) with D-Z″ as

Specific examples of monomer-bioactive moiety conjugates are shownbelow, with the bioactive moiety being presented on the left and themonomer-bioactive moiety conjugate being presented on the right:

Further specific examples of monomer-bioactive moiety conjugates areshown below, with the bioactive moiety being presented on the left andthe monomer-bioactive moiety conjugate being presented on the right. Theacetylated latanoprost monomer-bioactive moiety conjugates (lowerstructures) represent examples of bioactive moieties conjugated inprodrug form such that the acetyl groups will cleave in vivo:

In one aspect, the invention provides a method for preparing abiodegradable polymer according to the invention, said method comprisingthe step of polymerising a monomer-bioactive moiety conjugate of formula(II):

where: X′, Y′, R, Z and D are as herein defined;with at least one monomer comprising compatible chemical functionality.

The invention also provides a method for preparing a polymer-bioactiveagent conjugate comprising as part of its polymer backbone a moiety ofgeneral formula (Id):

wherein:

-   -   A and B, which may be the same or different, represent the        remainder of the polymer backbone and are selected from a        copolymer of polyurethane and polyester;    -   R represents a linear or branched optionally substituted        hydrocarbon;    -   Z is a linking group; and    -   D is a releasable bioactive moiety;        said process comprising the step of polymerising a monomer of        formula (IIa):

wherein:

-   -   R, Z and D are as defined above;        with at least one other monomer comprising compatible chemical        functionality.

The at least one other monomer preferably comprises a compatiblechemical functional group selected from the group consisting ofisocyanate, carboxylic acid, carboxylic acid halide, ester, anhydride(including cyclic anhydride) groups and combinations thereof. In someembodiments the monomer of formula (II) or (IIa) is polymerised with apolyisocyanate and at least one selected from the group consisting of apolyacid, a polyester, and a polyester polyol. In one form of theinvention, the monomer of formula (II) or (IIa) is polymerised with apolyisocyanate and a polyester polyol.

In a further aspect, the invention provides a method for preparing thebiodegradable polymer according to the invention by providing at leastone first monomer comprising at least one releasable bioactive moietyand at least one polymerisable moiety; optionally providing at least onesecond monomer comprising at least one polymerisable moiety reactivewith at least one polymerisable moiety of said first monomer;polymerising said first monomer and optionally said second monomeroptionally in the presence of one or more spacer moieties comprising twoor more functionalities under conditions which are substantiallynon-interfering to the therapeutic efficacy of the bioactive moieties.

Techniques, equipment and reagents well known in the art canadvantageously be used to prepare the polymer-bioactive moietyconjugates in accordance with the invention.

For example, polyurethanes might be prepared batch wise by mixing allcomponents together and waiting until an exotherm occurs followed bycasting the mixture into a container. The mixture can be subsequentlyheated to drive the reaction. When adopting this approach, thecomponents to be mixed might first be made up into two parts beforemixing: Part-1 might include a compound of general formula (II) whereboth X′ and Y′ are hydroxyl groups and one or more of: a polyol (e.g.polyester polyol), a chain extender, blowing agent (e.g. water),catalyst, and surfactants etc. Part-2 will generally comprise thepolyisocyanate. Part-1 or Part-2 can also contain other additives suchas fillers, pigments etc.

The polyurethanes might also be prepared as a prepolymer that issubsequently reacted with a chain extender. For example, throughsuitable adjustment of molar ratios, an isocyanate terminatedpre-polymer may be prepared by mixing Parts-1 and -2 mentioned above.The isocyanate terminated polymer could then be reacted with a chainextender/branching molecule such as a short chain diol (e.g.1,4-butanediol), polyol (such as a triol), a hydroxy acid (such aslactic acid or glycolic acid, or combinations thereof) or an estercontaining monomer or macromonomer (such as a ester linked dimer, trimeror oligomer of two or more hydroxy acids). Alternatively, throughsuitable adjustment of molar ratios, the prepolymer could be producedsuch that it was hydroxy terminated. This hydroxy terminated prepolymercould then be reacted with a polyisocyanate to produce the desiredpolyurethane.

The polyurethane forming reactions can be carried out in a range ofdifferent equipment including batch kettles, static mixers, reactiveinjection moulders or extruders.

It also may be advantageous to heat the reagents prior to or during thereaction process to improve their solubility or to enhance theirreactivity. The reaction process may also be conducted in solvent.

Suitable polyisocyanates that may be used to prepare thepolymer-bioactive moiety conjugates include aliphatic, aromatic andcycloaliphatic polyisocyanates and combinations thereof. Specificpolyisocyanates include, but are not limited to, diisocyanates such asm-phenylene diisocyanate, p-phenylene diisocyanate, 2,4-toluenediisocyanate, 2,6-toluene diisocyanate, 1,6-hexamethylene diisocyanate,1,4-hexamethylene diisocyanate, 1,3-cyclohexane diisocyanate,1,4-cyclohexane diisocyanate, hexahydro-toluene diisocyanate and itsisomers, isophorone diisocyanate, dicyclo-hexylmethane diisocyanates,1,5-napthylene diisocyanate, 4,4′-diphenylmethane diisocyanate,2,4′diphenylmethane diisocyanate, 4,4′-biphenylene diisocyanate,3,3′-dimethoxy-4,4′-biphenylene diisocyanate, and3,3′-dimethyl-diphenylpropane-4,4′-diisocyanate; triisocyanates such as2,4,6-toluene triisocyanate; higher-isocyanates such as4,4′-dimethyl-diphenylmethane-2,2′,5,5′-tetraisocyanate, polymethylenepolyphenyl-polyisocyanates and alkyl esters of lysine diisocyanate (forexample ethyl ester of lysine diisocyanate—ELDI); and combinationsthereof. It will be appreciated that the use of polyisocyanatescomprising greater than two isocyanate moieties provides for branchedstructures.

Polyesters might be prepared batch wise by mixing all componentstogether with heating and continued stirring. A condensate of thereaction such as water or low molecular weight alcohol (depending ifacids or esters are used as the co-monomer) can be removed bydistillation. To promote further reaction produce higher molecularweight polyester the temperature may be increased and vacuum applied.

A polycondensation catalyst well known to those skilled in the art canbe included in the reaction mixture to increase the rate ofpolymerisation.

The reaction may also be conducted in an appropriate solvent to helpincrease the rate of polymerisation. The solvent will generally beselected to have only minimal solubility with the condensate (e.g. wateror low molecular weight alcohol). For example the reaction may becarried out in toluene and a toluene/condensate mixture distilled offcontinuously and the condensate allowed to separate in a Dean-Starktrap.

To further increase the molecular weight of the polyester a second stagereaction in either a wiped film reactor or a solid state reactor may beemployed. The need to use such reactors will depend upon the targetmolecular weight as well as the suitability of the polymer for furtherreaction.

Suitable polyacids that may be used to prepare the polymer-bioactivemoiety conjugates include aliphatic, aromatic and cycloaliphaticpolyacids and combinations thereof. Specific polyacids include, but arenot limited to the following, oxalic acid, fumaric acid, maleic acid,succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid,azelaic acid, sebacic acid, phthalic acid, dodecanediacid, isophthalicacid, terephthalic acid, dodecylsuccinic acid,napthalene-2,6-dicarboxylic acid, naphthalene-2,7-dicarboxylic acid,cyclohexane dicarboxylic acid, fumaric acid, itaconic acid, malonicacid, mesaconic acid. Esters, diesters and anhydrides of the abovediacids are also suitable in the process of the invention.

Where the polyesters are prepared using a carboxylic acid halidemonomer, those skilled in the art will appreciate that the condensationreaction is driven by the removal of HX (where X is a halide). Forexample, if a di-acid chloride co-monomer is with the monomer-bioactivemoiety conjugate of formula (II) where both X′ and Y″ are hydroxylgroups, HCl will be liberated from the reaction. Such a reaction may becarried out in solution at an elevated temperature to drive thereaction. It is also possible to add an appropriate base to form a saltwith the liberated acid halide. For example an excess of triethyl aminemay be included in a reaction mixture containing a 1:1 molar ratio of adi-acid chloride co-monomer and the monomer-bioactive moiety conjugateof formula (II) where both X′ and Y″ are hydroxyl groups. The reactionwill afford the desired polymer-bioactive moiety conjugate and atriethyl-amine hydrochloride salt.

With all such polycondensation reactions, it is possible to some extentto control the molecular weight of the resulting polyester, its degreeof branching (through control of monomer functionality) and its endgroup functionality by adjustment of the molar ratio's and thefunctionality of the monomers used in the reaction.

For example, in some instances it may be desirable to produce lowermolecular weight polyesters that could be used as polymer-bioactivemoiety conjugate polyester polyols for reaction with polyisocyanates andperhaps other reagents for the production of polyester-urethanes.

Additionally, it may be possible to increase the molecular weight and/ordegree of branching of the polyester through the inclusion in thereaction mixture of coupling/branching agents. Examples of suchcoupling/branching agents include: polyepoxides, polyisocyanates,polyoxazolines. The term “poly” is used to indicate a reactivefunctionality of 2 or more (e.g. 2 or more epoxy groups). Having areactive functionality of 2 will tend to produce higher molecularpolymers still with a significant polyester-like character. Agentshaving a functionality of more than 2 will produce a branched polymer,still with significant polyester-like character.

A poly(urethane-ester) might be prepared by polymerising a diisocyanatewith a hydroxy terminated polyester polyol macromer. In that case, thepolyester polyol macromer will be formed from monomeric units that arecoupled via a biodegradable ester moiety, and the polymerisation of itwith the diisocyanate will give rise to the poly(urethane-ester) havingmonomeric units that are all coupled via a biodegradable urethane orester moiety.

Suitable polyester polyols may be selected from the group consisting ofpolycaprolactone diol (PCLD), poly(DL lactide) (DLLA) and poly(lacticacid-co-glycolic acid) (PLGA), and combinations thereof.

A poly(ester-urethane) might be prepared by polymerising an isocyanateterminated polyurethane macromer with an ester containing monomer ormacromonomer. The ester containing monomer or macromonomer may be formedfrom the condensation of two or more hydroxy acids. In one form, theester containing monomer is an ester linked dimer of two hydroxy acids.Suitable hydroxy acids include lactic acid, glycolic acid, andcombinations thereof. The polyurethane macromer will be formed frommonomeric units that are coupled via a biodegradable urethane moiety,and the polymerisation of it with the ester containing monomer ormacromonomer will give rise to the poly(ester-urethane) having monomericunits that are all coupled via a biodegradable urethane or ester moiety.

As discussed in more detail in the Example section below, the synthesismonomer bioactive moiety conjugates typically required the optimizationof reaction conditions and the alteration of known purificationmethodologies. The desired hydrolytic instability of the monomerbioactive moiety conjugates restricted the usage of several traditionalpurification methodologies and made the development of alternativepathways necessary.

The presence of any impurities in the monomer bioactive moietyconjugates can also affect the molecular weight, and structure of thefinal polymer as well as the release rate of the bioactive moiety fromthe polymer conjugate.

Further, the use of the monomer bioactive moiety conjugates in theformation of the polymers in some cases required specific polymerisationmethodology to be developed to allow the efficient incorporation of themonomer bioactive moiety conjugates into the polymer. This includedselection of appropriate solvents/heating/mixing/catalyst/order ofmonomer additions etc to allow the incorporation of the monomerbioactive moiety conjugates as well as to minimise the amount ofdegradation or premature release of the bioactive moiety.

Careful selection of co-monomers/reaction conditions etc may also berequired for a given monomer bioactive moiety conjugate in order toproduce a polymer conjugate with appropriate bioactive moiety loading aswell as have mechanical properties, bioactive moiety release rate,formability etc.

Additionally, methods were developed to remove impurities from thepolymer bioactive moiety conjugates in order provide control of therelease rate of the bioactive moiety from the polymer conjugate.

Irrespective of the manner in which the biodegradable polymer-bioactivemoiety conjugates are prepared, as discussed above all repeat units thatmake up the polymer backbone will be coupled via a biodegradable moiety.Accordingly, any monomer or macromer used in the preparation of theconjugates shall not contain repeat units that are coupled by anon-biodegradable moiety such as an ether.

While the use of polyether segments can provide desirable improvementsin the flexibility and in some cases can provide an improvement in thedesired rate of release of the bioactive the release of polyethershaving a molecular weight below 1000 g/mol can result in increasedtoxicity from the degradation products.

In most cases it is possible to use polyester polyols such aspolycaprolactone diol to also provide desired increase in theflexibility of the polymer as well as providing improvements in therelease of the bioactive agent. However, the polyester polyols canadvantageously degrade into more benign monomeric components.

Additionally the use of polyester polyols such as DLLA (DL lactide) orPLGA (poly(lactic-co-glycolic acid)) can provide an increase rate ofdegradation of the polymer as well as release of the drug through theautocatalytic effect of the released acidic components.

The biodegradable polymer may be formed and delivered as a liquid/waxthat can be injected, polymerised, cured, set or solidified in situ.

In one embodiment, the methods of the invention allow the formation ofbiodegradable moieties with multiple bioactive moieties, known loadings,evenly distributed bioactive moieties in the polymer chain,predetermined relative proportions and predetermined relative positions.

Scheme 3 illustrates the method with a valproic acid-polyurethaneconjugate.

Scheme 4 illustrates the method with a ciprofloxacin-polyurethaneconjugate.

Schemes 5 and 6 illustrate the method with a ciprofloxacin-polyesterconjugate and a valproic acid-polyester conjugate respectively.

The composition of the polymer can be advantageously altered toincorporate other monomers to provide appropriate polymer properties tosuit a particular application (e.g. hydrophobicity, structural strength,rate of release of bioactive moieties).

A further advantage is that side chain and end functional attachment ofthe bioactive moiety to the polymer (by control of the monomerstructure) allows the control of the polymer mechanical and otherproperties. In this sense the polymer therapeutic can be viewed and usedas a scaffold.

In a further aspect the control of the mechanical properties in that thebioactive moiety attached to the polymer may have differentmechanical/surface properties in the bioactive moiety attached statecompared to when the bioactive moiety is not attached, i.e., (i) as thebioactive moiety is released the polymer may alter in properties and(ii) forming a polymer from monomers functionalised with bioactivemoieties may have different (more desirable) properties compared to ananalogous polymer without bioactive moiety functionalisation (i.e.,bioactive moiety functionalisation breaks up the crystallinity toproduce a more flexible polymer).

The physical properties of final material can be altered throughchanging the composition of the polymer backbone.

The biodegradable polymers of the present invention may be blended withone or more other polymers (generally biodegradable polymers).

The present invention also provides a monomer comprising: a) one or morereleasable bioactive moieties; b) one or more polymerisable moieties;wherein one or more of the releasable bioactive moieties are capable ofbeing released from the monomer before or after polymerisation underconditions which are non-interfering to the therapeutic efficacy of thebioactive moieties.

The skilled artisan would be able to select suitable chemistry so asprotect other functionalities on the bioactive moieties duringattachment to the spacer or monomer during or after polymerisation.

There follows potential Schemes 7 and 8 for the protection/deprotectionand breakdown of polymer-bioactive moiety conjugates of the invention.Examples are illustrated for Ciprofloxacin attached to a polyurethane orto a polyester.

In one embodiment a biodegradable polymer of the present invention maybe prepared by the polymerisation of a hydroxy functionalised ester ofvalproic acid and a diisocyanate in the presence of a suitable catalyst.

A biodegradable polymer of the present invention may also be prepared bythe polymerisation of a dihydroxy functionalised ester of valproic acid,2,3-dihydroxypropyl-2-propylpentanoate, with hexamethyldiisocyanate inthe presence of a suitable catalyst.

In a further aspect there is provided a functionalised biodegradablepolymer comprising a plurality of labile bioactive moieties pendant fromand chemically bonded to a polymer backbone wherein the rate ofbioactive moiety release from the polymer backbone is equal to or fasterthan the rate of polymer backbone breakdown and wherein the polymerbackbone is substantially degradable.

The biodegradable polymers in accordance with the invention can beincorporated or made into coatings and scaffolds for target in vitro andin vivo applications in a variety of ways.

For example, the biodegradable polymers of the invention may be used inthe manufacture of sutures, dental devices, orthopaedic fixationdevices, transdermal patches, ligating clips, vascular grafts, stents,and tissue-engineering scaffolds. The polymers may be applied to theoutside or inside of the body of the subject in need of treatment.

In one embodiment, the biodegradable polymers of the invention may beused in the manufacture of an ocular implant. In some embodiments, theocular implant comprises a biodegradable polymer as described herein,where the bioactive moiety is a fluoroquinolone antibiotic. Preferredfluoroquinoline antibiotics include levofloxacin and moxifloxacin.

The present invention also provides a method for treating an eyecondition in a subject by administering a biodegradable polymer asdescribed herein to the subject, where the bioactive moiety is selectedfrom fluoroquinoline antibiotics. The eye condition may be an eyeinfection. In one form of the invention, the biodegradable polymer isadministered in an ocular implant. For the effective treatment of an eyeinfection, it would be desirable for the biodegradable polymer torelease an amount of fluoroquinolone antibiotic selected from the groupconsisting of at least 5 μg/24 hours, at least 10 μg/24 hours, at least15 μg/24 hours, and at least 20 μg/24 hours. Preferred fluoroquinolineantibiotics include levofloxacin and moxifloxacin.

Coatings containing the biodegradable polymers can advantageously bedirectly produced using techniques well known in the art including:solution casting, spray coating, melt pressing, transfer moulding,lamination, moulding onto a premade film containing the conjugate,rotomoulding, spin coating, extrusion coating, electrospinning etc.

Premade films for use in subsequent application as coatings canadvantageously also be produced using techniques well known in the artincluding: film extrusion, film blowing, tentering etc.

The premade films may be applied as coatings by: melt pressing, vacuumforming, thermoforming, transfer lamination, adhesive bonding.

Coatings may be included as films, multilayer films, non-uniform orgraded coatings as dots, patterns or structures according to some formof mask or template.

Three dimensional scaffolds containing the polymer-bioactive moietyconjugate(s) can also be formed in a number of means including:

-   -   Fibre based structures which in turn are knitted, woven,        spunbonded or formed into non-woven mats etc. Additionally,        fibre structures could be formed with a binder resin into        composite structures. The fibres could be formed by melt        extrusion, wet spinning or the bioactive conjugate could be        over-coated or dispersed within fibres by bicomponent fibre        extrusion, dip or spray coating etc.    -   Moulded structures could be produced by injection moulding, blow        moulding, reactive injection moulding, casting or moulding with        subsequent machining etc.    -   Porous structures could be made by moulding/extrusion in the        presence of the porogen. Additionally porous 3D structures could        be produced by moulding or polymerisation in the presence of an        extractable material. For example, a polyurethane containing the        monomer-bioactive moiety conjugate or polymer-bioactive moiety        conjugate could be formed by casting around a sufficient content        of polystyrene beads. The polystyrene beads could be removed by        extraction with an appropriate solvent.

In this specification “optionally substituted” is taken to mean that agroup may or may not be substituted or fused (so as to form a condensedpolycyclic group) with one, two, three or more of organic and inorganicgroups (i.e. the optional substituent) including those selected from:alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl,acyl, aralkyl, alkaryl, alkheterocyclyl, alkheteroaryl, alkcarbocyclyl,halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, halocarbocyclyl,haloheterocyclyl, haloheteroaryl, haloacyl, haloaryalkyl, hydroxy,hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycarbocyclyl,hydroxyaryl, hydroxyheterocyclyl, hydroxyheteroaryl, hydroxyacyl,hydroxyaralkyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl,alkoxycarbocyclyl, alkoxyaryl, alkoxyheterocyclyl, alkoxyheteroaryl,alkoxyacyl, alkoxyaralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,carbocyclyloxy, aralkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy,haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloaryloxy,halocarbocyclyloxy, haloaralkyloxy, haloheteroaryloxy,haloheterocyclyloxy, haloacyloxy, nitro, nitroalkyl, nitroalkenyl,nitroalkynyl, nitroaryl, nitroheterocyclyl, nitroheteroayl,nitrocarbocyclyl, nitroacyl, nitroaralkyl, amino(NH₂), alkylamino,dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino,aralkylamino, diaralkylamino, acylamino, diacylamino, heterocyclamino,heteroarylamino, carboxy, carboxyester, amido, alkylsulphonyloxy,arylsulphenyloxy, alkylsulphenyl, arylsulphenyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, aralkylthio, carbocyclylthio,heterocyclylthio, heteroarylthio, acylthio, sulfoxide, sulfonyl,sulfonamide, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocarbocyclyl,aminoaryl, aminoheterocyclyl, aminoheteroaryl, aminoacyl, aminoaralkyl,thioalkyl, thioalkenyl, thioalkynyl, thiocarbocyclyl, thioaryl,thioheterocyclyl, thioheteroaryl, thioacyl, thioaralkyl, carboxyalkyl,carboxyalkenyl, carboxyalkynyl, carboxycarbocyclyl, carboxyaryl,carboxyheterocyclyl, carboxyheteroaryl, carboxyacyl, carboxyaralkyl,carboxyesteralkyl, carboxyesteralkenyl, carboxyesteralkynyl,carboxyestercarbocyclyl, carboxyesteraryl, carboxyesterheterocyclyl,carboxyesterheteroaryl, carboxyesteracyl, carboxyesteraralkyl,amidoalkyl, amidoalkenyl, amidoalkynyl, amidocarbocyclyl, amidoaryl,amidoheterocyclyl, amidoheteroaryl, amidoacyl, amidoaralkyl,formylalkyl, formylalkenyl, formylalkynyl, formylcarbocyclyl,formylaryl, formylheterocyclyl, formylheteroaryl, formylacyl,formylaralkyl, acylalkyl, acylalkenyl, acylalkynyl, acylcarbocyclyl,acylaryl, acylheterocyclyl, acylheteroaryl, acylacyl, acylaralkyl,sulfoxidealkyl, sulfoxidealkenyl, sulfoxidealkynyl,sulfoxidecarbocyclyl, sulfoxidearyl, sulfoxideheterocyclyl,sulfoxideheteroaryl, sulfoxideacyl, sulfoxidearalkyl, sulfonylalkyl,sulfonylalkenyl, sulfonylalkynyl, sulfonylcarbocyclyl, sulfonylaryl,sulfonylheterocyclyl, sulfonylheteroaryl, sulfonylacyl, sulfonylaralkyl,sulfonamidoalkyl, sulfonamidoalkenyl, sulfonamidoalkynyl,sulfonamidocarbocyclyl, sulfonamidoaryl, sulfonamidoheterocyclyl,sulfonamidoheteroaryl, sulfonamidoacyl, sulfonamidoaralkyl, nitroalkyl,nitroalkenyl, nitroalkynyl, nitrocarbocyclyl, nitroaryl,nitroheterocyclyl, nitroheteroaryl, nitroacyl, nitroaralkyl, cyano,sulfate and phosphate groups.

In some embodiments, it may be desirable that a group (for example the Rgroup) is optionally substituted with a polymer chain. An example ofsuch a polymer chain includes a polyester, polyurethane, or copolymersthereof. Such a polymer chain may, or may not, have one or morebioactive moieties appended thereto. For example, the R group of theformulae disclosed herein may be substituted with a polymer chain. Theskilled worker will recognise that the R group may therefore represent apoint of branching of the polymer backbone within the polymer-bioactivemoiety conjugate of the present invention. If R is substituted with apolymer chain, that polymer chain should also be biodegradable and notcontain any repeat units that are coupled with a non-biodegradablemoiety as described herein.

Preferred optional substituents include the aforementioned reactivefunctional groups or moieties, polymer chains and alkyl, (e.g. C₁₋₆alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl), hydroxyalkyl (e.g. hydroxymethyl,hydroxyethyl, hydroxypropyl), alkoxyalkyl (e.g. methoxymethyl,methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyletc) alkoxy (e.g. C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy, butoxy,cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl,tribromomethyl, hydroxy, phenyl (which itself may be further substitutede.g., by C₁₋₆ alkyl, halo, hydroxy, hydroxyC₁₋₆ alkyl, C₁₋₆ alkoxy,haloC₁₋₆alkyl, cyano, nitro OC(O)C₁₋₆ alkyl, and amino), benzyl (whereinbenzyl itself may be further substituted e.g., by C₁₋₆ alkyl, halo,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl, cyano, nitroOC(O)C₁₋₆ alkyl, and amino), phenoxy (wherein phenyl itself may befurther substituted e.g., by C₁₋₆ alkyl, halo, hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl, cyano, nitro OC(O)C₁₋₆ alkyl, andamino), benzyloxy (wherein benzyl itself may be further substitutede.g., by C₁₋₆ alkyl, halo, hydroxy, hydroxyC₁₋₆ alkyl, C₁₋₆ alkoxy,haloC₁₋₆ alkyl, cyano, nitro OC(O)C₁₋₆ alkyl, and amino), amino,alkylamino (e.g. C₁₋₆ alkyl, such as methylamino, ethylamino,propylamino etc), dialkylamino (e.g. C₁₋₆ alkyl, such as dimethylamino,diethylamino, dipropylamino), acylamino (e.g. NHC(O)CH₃), phenylamino(wherein phenyl itself may be further substituted e.g., by C₁₋₆ alkyl,halo, hydroxy hydroxyC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl, cyano,nitro OC(O)C₁₋₆ alkyl, and amino), nitro, formyl, —C(O)-alkyl (e.g. C₁₋₆alkyl, such as acetyl), O—C(O)-alkyl (e.g. C₁₋₆ alkyl, such asacetyloxy), benzoyl (wherein the phenyl group itself may be furthersubstituted e.g., by C₁₋₆ alkyl, halo, hydroxy hydroxyC₁₋₆ alkyl, C₁₋₆alkoxy, haloC₁₋₆ alkyl, cyano, nitro OC(O)C₁₋₆alkyl, and amino),replacement of CH₂ with C═O, CO₂H, CO₂ alkyl (e.g. C₁₋₆ alkyl such asmethyl ester, ethyl ester, propyl ester, butyl ester), CO₂-phenyl(wherein phenyl itself may be further substituted e.g., by C₁₋₆ alkyl,halo, hydroxy, hydroxyl C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, cyano,nitro OC(O)C₁₋₆ alkyl, and amino), CONH₂, CONHphenyl (wherein phenylitself may be further substituted e.g., by C₁₋₆ alkyl, halo, hydroxy,hydroxyl C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, cyano, nitroOC(O)C₁₋₆ alkyl, and amino), CONHbenzyl (wherein benzyl itself may befurther substituted e.g., by C₁₋₆ alkyl, halo, hydroxy hydroxyl C₁₋₆alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, cyano, nitro OC(O)C₁₋₆ alkyl, andamino), CONHalkyl (e.g. C₁₋₆ alkyl such as methyl ester, ethyl ester,propyl ester, butyl amide) CONHdialkyl (e.g. C₁₋₆ alkyl) aminoalkyl(e.g., HN C₁₋₆ alkyl-, C₁₋₆alkylHN—C₁₋₆ alkyl- and (C₁₋₆ alkyl)₂N—C₁₋₆alkyl-), thioalkyl (e.g., HS C₁₋₆ alkyl-), carboxyalkyl (e.g., HO₂CC₁₋₆alkyl-), carboxyesteralkyl (e.g., C₁₋₆ alkylO₂CC₁₋₆ alkyl-), amidoalkyl(e.g., H₂N(O)CC₁₋₆ alkyl-, H(C₁₋₆ alkyON(O)CC₁₋₆ alkyl-), formylalkyl(e.g., OHCC₁₋₆alkyl-), acylalkyl (e.g., C₁₋₆ alkyl(O)CC₁₋₆ alkyl-),nitroalkyl (e.g., O₂NC₁₋₆ alkyl-), sulfoxidealkyl (e.g., R³(O)SC₁₋₆alkyl, such as C₁₋₆ alkyl(O)SC₁₋₆ alkyl-), sulfonylalkyl (e.g.,R³(O)₂SC₁₋₆ alkyl- such as C₁₋₆ alkyl(O)₂SC₁₋₆ alkyl-), sulfonamidoalkyl(e.g., ₂HRN(O)SC₁₋₆ alkyl, H(C₁₋₆ alkyl)N(O)SC₁₋₆ alkyl-).

As used herein, the term “alkyl”, used either alone or in compound wordsdenotes straight chain, branched or cyclic alkyl, for example C₁₋₄₀alkyl, or C₁₋₂₀ or C₁₋₁₀. Examples of straight chain and branched alkylinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl,n-pentyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl,4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl,1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl,2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl,1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl,6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-,3-, 4-, 5-, 6- or 7-methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2-or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl,1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl,undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-,4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-,9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-,2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl,1-2-pentylheptyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, nonoadecyl, eicosyl and the like. Examples ofcyclic alkyl include mono- or polycyclic alkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group isreferred to generally as “propyl”, butyl” etc, it will be understoodthat this can refer to any of straight, branched and cyclic isomerswhere appropriate. An alkyl group may be optionally substituted by oneor more optional substituents as herein defined.

As used herein, term “alkenyl” denotes groups formed from straightchain, branched or cyclic hydrocarbon residues containing at least onecarbon to carbon double bond including ethylenically mono-, di- orpolyunsaturated alkyl or cycloalkyl groups as previously defined, forexample C₂₋₄₀ alkenyl, or C₂₋₂₀ or C₂₋₁₀. Thus, alkenyl is intended toinclude propenyl, butylenyl, pentenyl, hexaenyl, heptaenyl, octaenyl,nonaenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl,pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nondecenyl,eicosenyl hydrocarbon groups with one or more carbon to carbon doublebonds. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl,iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl,1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl,3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl,1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl,1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl,1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl,1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. An alkenyl groupmay be optionally substituted by one or more optional substituents asherein defined.

As used herein the term “alkynyl” denotes groups formed from straightchain, branched or cyclic hydrocarbon residues containing at least onecarbon-carbon triple bond including ethylenically mono-, di- orpolyunsaturated alkyl or cycloalkyl groups as previously defined, forexample, C₂₋₄₀ alkenyl, or C₂₋₂₀ or C₂₋₁₀. Thus, alkynyl is intended toinclude propynyl, butylynyl, pentynyl, hexaynyl, heptaynyl, octaynyl,nonaynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl,pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nondecynyl,eicosynyl hydrocarbon groups with one or more carbon to carbon triplebonds. Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, andbutynyl isomers, and pentynyl isomers. An alkynyl group may beoptionally substituted by one or more optional substituents as hereindefined.

An alkenyl group may comprise a carbon to carbon triple bond and analkynyl group may comprise a carbon to carbon double bond (i.e. socalled ene-yne or yne-ene groups).

As used herein, the term “aryl” (or “carboaryl)” denotes any of single,polynuclear, conjugated and fused residues of aromatic hydrocarbon ringsystems. Examples of aryl include phenyl, biphenyl, terphenyl,quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl,dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl,fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl. Preferred aryl includephenyl and naphthyl. An aryl group may be optionally substituted by oneor more optional substituents as herein defined.

As used herein, the terms “alkylene”, “alkenylene”, and “arylene” areintended to denote the divalent forms of “alkyl”, “alkenyl”, and “aryl”,respectively, as herein defined.

The term “halogen” (“halo”) denotes fluorine, chlorine, bromine oriodine (fluoro, chloro, bromo or iodo). Preferred halogens are chlorine,bromine or iodine.

The term “carbocyclyl” includes any of non-aromatic monocyclic,polycyclic, fused or conjugated hydrocarbon residues, preferably C₃₋₂₀(e.g. C₃₋₁₀ or C₃₋₈). The rings may be saturated, e.g. cycloalkyl, ormay possess one or more double bonds (cycloalkenyl) and/or one or moretriple bonds (cycloalkynyl). Particularly preferred carbocyclyl moietiesare 5-6-membered or 9-10 membered ring systems. Suitable examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl,cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctatetraenyl,indanyl, decalinyl and indenyl.

The term “heterocyclyl” when used alone or in compound words includesany of monocyclic, polycyclic, fused or conjugated hydrocarbon residues,preferably C₃₋₂₀ (e.g. C₃₋₁₀ or C₃₋₈) wherein one or more carbon atomsare replaced by a heteroatom so as to provide a non-aromatic residue.Suitable heteroatoms include O, N, S, P and Se, particularly O, N and S.Where two or more carbon atoms are replaced, this may be by two or moreof the same heteroatom or by different heteroatoms. The heterocyclylgroup may be saturated or partially unsaturated, i.e. possess one ormore double bonds. Particularly preferred heterocyclyl are 5-6 and 9-10membered heterocyclyl. Suitable examples of heterocyclyl groups mayinclude azridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,2H-pyrrolyl, pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl,morpholinyl, indolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,thiomorpholinyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyrrolyl, tetrahydrothiophenyl, pyrazolinyl, dioxalanyl,thiazolidinyl, isoxazolidinyl, dihydropyranyl, oxazinyl, thiazinyl,thiomorpholinyl, oxathianyl, dithianyl, trioxanyl, thiadiazinyl,dithiazinyl, trithianyl, azepinyl, oxepinyl, thiepinyl, indenyl,indanyl, 3H-indolyl, isoindolinyl, 4H-quinolazinyl, chromenyl,chromanyl, isochromanyl, pyranyl and dihydropyranyl.

The term “heteroaryl” includes any of monocyclic, polycyclic, fused orconjugated hydrocarbon residues, wherein one or more carbon atoms arereplaced by a heteroatom so as to provide an aromatic residue. Preferredheteroaryl have 3-20 ring atoms, e.g. 3-10. Particularly preferredheteroaryl are 5-6 and 9-10 membered bicyclic ring systems. Suitableheteroatoms include, O, N, S, P and Se, particularly O, N and S. Wheretwo or more carbon atoms are replaced, this may be by two or more of thesame heteroatom or by different heteroatoms. Suitable examples ofheteroaryl groups may include pyridyl, pyrrolyl, thienyl, imidazolyl,furanyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl,indolyl, isoindolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolizinyl, quinolyl, isoquinolyl, phthalazinyl, 1,5-naphthyridinyl,quinozalinyl, quinazolinyl, quinolinyl, oxazolyl, thiazolyl,isothiazolyl, isoxazolyl, triazolyl, oxadialzolyl, oxatriazolyl,triazinyl, and furazanyl.

The term “acyl” either alone or in compound words denotes a groupcontaining the agent C═O (and not being a carboxylic acid, ester oramide) Preferred acyl includes C(O)—R^(x), wherein R^(x) is hydrogen oran alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, orheterocyclyl residue. Examples of acyl include formyl, straight chain orbranched alkanoyl (e.g. C₁₋₂₀) such as, acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl,octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such ascyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl andcyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl;aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl,phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl)and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl andnaphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g.phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl andphenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl,naphthylbutenoyl and naphthylpentenoyl); aryloxyalkanoyl such asphenoxyacetyl and phenoxypropionyl; arylthiocarbamoyl such asphenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl andnaphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl andnapthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such asthienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl,thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl andtetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl,heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexanoyl;and heterocyclicglyoxyloyl such as thiazolyglyoxyloyl andthienylglyoxyloyl. The R^(x) residue may be optionally substituted asdescribed herein.

The term “sulfoxide”, either alone or in a compound word, refers to agroup —S(O)R^(y) wherein R^(y) is selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, andaralkyl. Examples of preferred R^(y) include C₁₋₂₀alkyl, phenyl andbenzyl.

The term “sulfonyl”, either alone or in a compound word, refers to agroup S(O)₂—R^(y), wherein R^(y) is selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl andaralkyl. Examples of preferred R^(y) include C₁₋₂₀alkyl, phenyl andbenzyl.

The term “sulfonamide”, either alone or in a compound word, refers to agroup S(O)NR^(y)R^(y) wherein each R^(y) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,carbocyclyl, and aralkyl. Examples of preferred R^(y) includeC₁₋₂₀alkyl, phenyl and benzyl. In a preferred embodiment at least oneR^(y) is hydrogen. In another form, both R^(y) are hydrogen.

The term, “amino” is used here in its broadest sense as understood inthe art and includes groups of the formula NR^(A)R^(B) wherein R^(A) andR^(B) may be any independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, aralkyl, and acyl.R^(A) and R^(B), together with the nitrogen to which they are attached,may also form a monocyclic, or polycyclic ring system e.g. a 3-10membered ring, particularly, 5-6 and 9-10 membered systems. Examples of“amino” include NH₂, NHalkyl (e.g. C₁₋₂₀alkyl), NHaryl (e.g. NHphenyl),NHaralkyl (e.g. NHbenzyl), NHacyl (e.g. NHC(O)C₁₋₂₀alkyl, NHC(O)phenyl),Nalkylalkyl (wherein each alkyl, for example C₁₋₂₀, may be the same ordifferent) and 5 or 6 membered rings, optionally containing one or moresame or different heteroatoms (e.g. O, N and S).

The term “amido” is used here in its broadest sense as understood in theart and includes groups having the formula C(O)NR^(A)R^(B), whereinR^(A) and R^(B) are as defined as above. Examples of amido includeC(O)NH₂, C(O)NHalkyl (e.g. C₁₋₂₀alkyl), C(O)NHaryl (e.g. C(O)NHphenyl),C(O)NHaralkyl (e.g. C(O)NHbenzyl), C(O)NHacyl (e.g.C(O)NHC(O)C₁₋₂₀alkyl, C(O)NHC(O)phenyl), C(O)Nalkylalkyl (wherein eachalkyl, for example C₁₋₂₀, may be the same or different) and 5 or 6membered rings, optionally containing one or more same or differentheteroatoms (e.g. O, N and S).

The term “carboxy ester” is used here in its broadest sense asunderstood in the art and includes groups having the formula CO₂R^(z),wherein R^(z) may be selected from groups including alkyl, alkenyl,alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, aralkyl, and acyl.Examples of carboxy ester include CO₂C₁₋₂₀alkyl, CO₂aryl (e.g.CO₂-phenyl), CO₂aralkyl (e.g. CO₂ benzyl).

The term “heteroatom” or “hetero” as used herein in its broadest senserefers to any atom other than a carbon atom which may be a member of acyclic organic group. Particular examples of heteroatoms includenitrogen, oxygen, sulfur, phosphorous, boron, silicon, selenium andtellurium, more particularly nitrogen, oxygen and sulfur.

It is understood that the compounds of the present invention (includingmonomers and polymers) may exist in one or more stereoisomeric forms (egenantiomers, diastereomers). The present invention includes within itsscope all of these stereoisomeric forms either isolated (in for exampleenantiomeric isolation), or in combination (including racemic mixtures).

The following examples are intended to illustrate the scope of theinvention and to enable reproduction and comparison. They are notintended to limit the scope of the disclosure in any way.

EXAMPLES General

Proton NMR spectra were obtained on Bruker AV400 and Bruker AV200spectrometers, operating at 400 MHz and 200 MHz respectively. Allspectra were obtained at 23° C. unless specified. Chemical shifts arereported in parts per million (ppm) on the δ scale and relative to thechloroform peak at 7.26 ppm (1H). Oven dried glassware was used in allreactions carried out under an inert atmosphere (either dry nitrogen orargon). All starting materials and reagents were obtained commerciallyunless otherwise stated. Removal of solvents “under reduced pressure”refers to the process of bulk solvent removal by rotary evaporation (lowvacuum pump) followed by application of high vacuum pump (oil pump) fora minimum of 30 min. Analytical thin layer chromatography (TLC) wasperformed on plastic-backed Merck Kieselgel KG60F254 silica plates andvisualised using short wave ultraviolet light, potassium permanganate orphosphomolybdate dip. Flash chromatography was performed using 230-400mesh Merck Silica Gel 60 following established guidelines under positivepressure. Tetrahydrofuran and dichloromethane were obtained from asolvent dispensing system under an inert atmosphere. All other reagentsand solvents were used as purchased.

Molecular weights of polymers were characterized by gel permeationchromatography (GPC) performed in tetrahydrofuran (THF) ordimethylformamide (DMF) 1.0 mL/min, 25° C. using a Waters GPCinstrument, with a Waters 2414 Refractive Index Detector, a series offour Polymer Laboratories PLGel columns (3×5 μm Mixed-C and 1×3 μmMixed-E), and Empower Pro Software. The GPC was calibrated with narrowpolydispersity polystyrene standards (Polymer Laboratories EasiCal, MWfrom 264 to 256000), and molecular weights are reported as polystyreneequivalents.

Acid number and hydroxy number were performed using the methods outlinedbelow

Valproic Acid (2-propylpentanoic Acid) Example 1 Valproic AcidMonoglyceride (VA-MG)—For comparative Examples (a) 2-propylpentanoicacid, 2,2-dimethyl-1,3-dioxolane-4-yl methyl ester

2-propylpentanoic acid (10.00 g; 0.07 mol) was dissolved indichloromethane (anhydrous) (500 ml), under an argon atmosphere.2,2-dimethyl-1,3-dioxolane-4-methanol (solketal) (11.00 g; 0.08 mol; 1.2equiv) and p-dimethylaminopyridine (1.02 g; 8.30 mmol; 0.12 equiv) wereadded. The solution was cooled to 0° C. and a solution of1,3-dicyclohexylcarbodiimide (17.17 g; 0.08 mol; 1.20 equiv) indichloromethane (anhydrous) (100 ml) was added dropwise over 30 minutes.A white precipitate formed during the addition. The reaction mixture wasallowed to warm to ambient temperature and stirred at ambienttemperature for 16 hours. The reaction mixture was cooled in a dryice/acetone bath (−78° C.) followed by filtration to remove the ureaprecipitate. The solvent was removed in vacuo to obtain the crudeproduct as a clear, colourless oil (23.29 g) which was purified bycolumn chromatography (silica gel, 5% ethyl acetate/petroleum ether40-60) to obtain a colourless oil (14.40 g, 80%).

¹H-NMR (CDCl₃, 200 MHz): δ[ppm]=4.30 (quintet, 1H, J=5.8 Hz); 4.03-4.17(m, 3H); 3.74 (dd, 1H, J=6.1 Hz, J=8.3 Hz); 2.34-2.47 (m, 1H); 1.19-1.69(m, 14H); 0.89 (t, 6H, J=7.1 Hz)

(b) 2,3-dihydroxypropyl 2-propylpentanoate (VA-MG)

2-propylpentanoic acid 2,2-dimethyl-1,3-dioxolane-4-yl methyl ester wasdissolved in 95% (v/v) aqueous ethanol (200 ml). Amberlyst 15 (wet) ionexchange resin (sulfonic acid) (6.40 g) and antibumping granules wereadded. The reaction mixture was refluxed for 5 hours without stirring.The reaction mixture was cooled to ambient temperature, followed byfiltration and removal of the solvent in vacuo to obtain a pale brownoil (12.89 g) which was purified by column chromatography (silica gel,50% ethyl acetate/petroleum ether 40-60) to obtain a colourless oil(10.40 g, 86%).

¹H-NMR (CDCl₃, 200 MHz): δ[ppm]=4.27-4.11 (m, 2H); 3.80-4.01 (m, 1H);3.52-3.76 (m, 2H); 2.52 (d, 1H, J=5.0 Hz); 2.34-2.49 (m, 1H); 2.09 (t,1H, J=6.0 Hz); 1.20-1.70 (8H); 0.90 (t, 6H, J=6.9 Hz)

Example 2 3-(1,3-dihydroxypropan-2-yloxy)-3-oxopropyl 2-propylpentanoatea) 3-hydroxypropyl 2-propylpentanoate

2-propylpentanoic acid (10.0 g, 69.3 mmol) was mixed withpropane-1-3-diol (42.1 g, 555.0 mmol) and methyl-sulfonic acid (5 drops)in toluene (200 ml) and the mixture was heated under reflux using a DeanStark trap for 12 h. After that, toluene was removed under reducedpressure and the crude mixture was dissolved in dichloromethane (200 ml)and extracted with water (pH 5, 3×200 ml). The combined organic layerswere dried over sodium sulfate and the volatiles were removed underreduced pressure giving a clear oil (14.0 g, 60.0 mmol, 99%).

¹H-NMR (CDCl₃, 200 MHz): δ[ppm]=4.24 (tr, 2H, J=6.1 Hz), 3.68 (tr, 2H,J=6.1 Hz), 2.37-2.31 (m, 1H), 1.93-1.77 (m, 2H), 1.69-1.16 (m, 8H), 0.89(tr, 6H, 6.9 Hz)

b) 3-(2-propylpentanoyloxy)propanoic acid

3-hydroxypropyl 2-propylpentanoate (2.08 g, 10.3 mmol) was dissolved in120 ml of acetone. 3.1 ml of a solution of Jones Reagent (prepared bydissolving 26.72 g of chromium trioxide in 23 ml of concentratedsulfuric acid, and then diluting the mixture to 100 ml with water) wasadded. Propan-2-ol (5 ml) was added to the reaction mixture which wasfiltered through a pad of celite. The filtrate was washed with 0.01M HClsolution (3×50 ml), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product (2.05 g, 9.5 mmol, 92%) wasused in the next step without any further purification.

¹H-NMR (CDCl₃, 200 MHz): δ[ppm]=4.35 (tr, 2H, J=6.3 Hz), 2.70 (tr, 2H,J=6.3 Hz), 2.47-2.28 (m, 1H), 1.70-1.15 (m, 8H), 0.88 (tr, 6H, J=6.9 Hz)

c) 3-oxo-3-(2-phenyl-1,3-dioxan-5-yloxy)propyl 2-propylpentanoate

3-(2-propylpentanoyloxy)propanoic acid (2.05 g, 9.5 mmol) was dissolvedin anhydrous CH₂Cl₂ (200 ml) under argon. 1,3-O-benzylideneglycerol(2.50 g, 13.67 mmol triethylamine (4.04 g, 40.0 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-trimethyluronium hexafluorophosphate (4.2g, 11.0 mmol) were added successively. The reaction mixture was stirredunder argon for 72 h. The reaction mixture was washed with saturatedNaHCO₃ solution (1×90 ml), water (1×90 ml) and dried over Na₂SO₄. Theorganic solvent was removed under reduced pressure giving a pale, pinksolid (2.99 g, 7.9 mmol, 83%).

¹H-NMR (CDCl₃, 200 MHz): δ[ppm]=7.63-7.29 (m, 5H), 5.55 (m, 5H),4.75-4.66 (m, 1H), 4.42-4.06 (m, 4H), 3.01-2.78 (m, 2H), 2.74-2.24 (m,3H), 2.07-1.18 (m, 8H), 0.92 (tr, 6H, J=6.9 Hz)

d) 3-(1,3-dihydroxypropan-2-yloxy)-3-oxopropyl 2-propylpentanoate

3-oxo-3-(2-phenyl-1,3-dioxan-5-yloxy)propyl 2-propylpentanoate (2.99 g,7.9 mmol) was dissolved in ethanol (90 ml) under argon. Palladiumcatalyst (10 wt % Pd/C) (300 mg) was added, the flask was evacuated andallowed to stir 1 atm of hydrogen gas at room temperature for 16 hours.The crude reaction mixture was passed through a glass microfiber on asintered funnel. The volatiles were removed under reduced pressureyielding 2.01 g (6.95 mmol, 88%) of a clear oil. The product was usedwithout any further purification

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=4.99-4.90 (m, 1H), 3.86-3.80 (m, 4H),2.80-2.70 (m, 2H), 2.48-2.37 (m, 2H), 1.89-1.80 (m, 2H), 1.68-1.54 (m,2H), 1.50-1.22 (m, 6H), 0.91 (tr, 6H, J=7.2 Hz)

Example 3 Production of a mixture of1,2-dihydroxy-5,14-dioxo-4,15-dioxa-6,13-diazanonadecan-19-yl2-propylpentanoate and1-hydroxy-2-(hydroxymethyl)-4,13-dioxo-3,14-dioxa-5,12-diazaoctadecan-18-yl2-propylpentanoate a) 4-hydroxybutyl 2-propylpentanoate

2-propylpentanoic acid (40.16 g, 278.5 mmol) was mixed withbutane-1-4-diol (114.65 g, 1272.2 mmol) and methyl-sulfonic acid (5drops) in toluene (3500 ml) and the mixture was heated under refluxusing a Dean Stark trap for 12 h. After that, toluene was removed underreduced pressure and the crude mixture was dissolved in chloroform (200ml) and extracted with water (pH 5, 3×200 ml). The combined organiclayers were dried over sodium sulfate and the volatiles were removedunder reduced pressure giving a clear oil (99%).

The product was analysed by NMR and found to be VA-BDO

b) 4-(6-isocyanatohexylcarbamoyloxy)butyl 2-propylpentanoate

Solution A: 4-hydroxybutyl 2-propylpentanoate (VA-BDO) (10.4518 g 48.3)mmol) was dried under vacuum and placed in a dried flask fitted with amagnetic stir bar and closed with a subaseal. The flask was also fittedwith a dry nitrogen gas purge line. Approximately 100 mL of chloroformwhich had been previously dried over molecular sieve was introduced tothe flask.

Solution B. hexamethylene diisocyanate (HDI) (7.900 μg 47.0 mmol) whichhad been distilled under vacuum was placed in a round bottom flaskfitted with a magnetic stir bar and closed with a subaseal. The flaskwas also fitted with a dry nitrogen gas purge line. Approximately 120 mLof chloroform which had been previously dried over molecular sieve wasintroduced to the flask. Additionally 5 drops of Tin 2-ethyl hexanoatewas added to the flask as a catalyst.

The content of Solution A was slowly added over a 15 minute period toSolution B with stirring.

The mixture was stirred overnight at room temperature under drynitrogen. The reaction mixture/solvent=Solution C

A 10 mL subsample was removed and the chloroform removed by under vacuumby rotovap. The compound was analysed by NMR in CDCl₃ and found tocontain a high proportion of 4-(6-isocyanatohexylcarbamoyloxy)butyl2-propylpentanoate (VA-BDO-HDL)

c) Mixture of1,2-dihydroxy-5,14-dioxo-4,15-dioxa-6,13-diazanonadecan-19-yl2-propylpentanoate and1-hydroxy-2-(hydroxymethyl)-4,13-dioxo-3,14-dioxa-5,12-diazaoctadecan-18-yl2-propylpentanoate

The remaining amount if Solution C from was added slowly over 15 mins toSolution D—which consisted of glycerol (4.4499 g 48.3 mmol) which wasdried overnight at 110 C under vacuum) and 100 mL dried chloroform.

The amount of glycerol in solution D was adjusted to give a 1:1 moleratio of VA-BDO-HDI to Glycerol, with a slight excess of glycerol.

The solution was stirred for 24 hours at 90 C under a nitrogen purge. Atvarious timepoints 4 Ml samples were removed and the chloroform wasremoved by rotovap and the products were analysed by NMR.

Once high conversion was confirmed by NMR the solution was cooled, morechloroform added to make up to 200 mL and extracted with water (pH 5,3×200 ml). The combined organic layers were dried over sodium sulfateand the volatiles were removed under reduced pressure giving a whitesolid

A subsample was dissolved in d-DMSO for analysis by NMR. The sampleappears to be a mixture of SN1 and SN2 coupling of the VA-BDO-HDI toGlycerol.

The product was dried and stored under nitrogen for use in theproduction of polymers.

Ciprofloxacin (1-cyclopropyl-6-fluoro-4-oxo-7-[4′-N-[(tert-butyloxy)carbonyl]piperazin]-1-yl-quinoline-3-carboxylic acid) Example 4Ciprofloxacin Monoglyceride (2,3-dihydroxypropyl1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate)a)7-(4-(benzyloxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

Ciprofloxacin(1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl)-1,4-quinoline-3-carboxylicacid (0.33 g, 1.0 mmol), was taken up in 2N NaOH solution (10 ml) andcooled to 0° C. (ice/water bath). Benzyloxycarbonyl chloride (0.40 ml,0.48 g, 2.8 mmol) was added dropwise. The reaction mixture was stirredat 0° C. for 1 h and then gradually warmed to room temperature andstirred for another 16 h. After that the reaction mixture was brought topH 5 through dropwise addition of 2N HCl solution. The reaction mixturewas extracted with CHCl₃ (3×50 ml). The combined organic layers weredried over Na₂SO₄ and the solvent was removed under reduced pressure.The crude product was purified through crystallisation from acetonitrileto give a colourless solid (0.23 g, 0.49 mmol, 49%)

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.78 (s, 1H, H-2); 8.10-8.00 (m, 1H,H-5); 7.44-7.28 (m, 6H, 1H of H-8+5H of ArH); 5.17 (s, 2H, ArCH₂ );3.81-3.63 (m, 4H, 2×CH₂ of piperazine); 3.56-3.46 (m, 1H ofcyclopropane); 3.38-3.23 (m, 4H, 2×CH₂ of piperazine); 1.44-1.33 (m, 2H,CH₂ of cyclopropane); 1.24-1.13 (m, 2H, CH₂ of cyclopropane)

b) (2,2-dimethyl-1,3-dioxolan-4-yl)methyl7-(4-(benzyloxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

7-(4-(benzyloxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (0.47 g, 1.0 mmol) was dissolved in anhydrous CH₂Cl₂ (47 ml) underargon. 2,2-dimethyl-1,3-dioxolane-4-methanol (0.20 g, 1.5 mmol)triethylamine (0.40 g, 4.0 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-trimethyluronium hexafluorophosphate (0.42g, 1.1 mmol) were added successively. The reaction mixture was stirredunder argon for 72 h. The reaction mixture was washed with saturatedNaHCO₃ solution (1×50 ml), water (1×50 ml) and dried over Na₂SO₄. Theorganic solvent was removed under reduced pressure, giving a pale, pinksolid (0.54 g, 0.93 mmol, 93%).

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.56 (s, 1H, H-2); 8.10-7.97 (m, 1H,H-5); 7.42-7.13 (m, 6H, 5×ArH+1H of H-8); 5.16 (s, 2H, ArCH₂O);4.52-4.40 (m, 1H, CH); 4.40-4.30 (m, 2H, 1H of CH₂O+1H of CH₂O);4.08-3.96 (m, 1H, 1H of CH₂O); 3.86-3.81 (m, 1H, 1H of CH₂O); 3.62-3.51(m, 4H, 2×CH₂ of piperazine); 3.37-3.33 (m, 1H, CH of cyclopropane);3.31-3.14 (m, 4H, 2×CH₂ of piperazine); 1.44 (s, 3H, CH₃); 1.36 (s, 3H,CH₃); 1.34-1.26 (m, CH₂ of cyclopropane); 1.26-1.03 (m, CH₂ ofcyclopropane)

MS (MeCN) 580 [M+1] 602 [M+23]

c) 2,3-dihydroxypropyl7-(4-(benzyloxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

(2,2-dimethyl-1,3-dioxolan-4-yl)methyl7-(4-(benzyloxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(2.85 g, 4.9 mmol) was dissolved in 95% aqueous ethanol (100 ml). Afteraddition of amberlyst 15 (wet) ion exchange resin and anti bumpinggranulates the reaction mixture was refluxed for 5 h. The ion exchangeresin and the bumping-granulates were removed through filtration and thesolvent was removed under reduced pressure to give the crude product asa yellow solid. The crude product was purified through columnchromatography (Al₂O₃ 1% MeOH in CHCl₃) to yield the pure product as apale yellow solid (1.66 g, 63%).

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.52 (s, 1H, H-2); 7.97-7.77 (m, 1H,H-5); 7.67-7.51 (m, 1H, H-8); 7.51-7.26 (m, 5H, ArH); 5.17 (s, 2H,ArCH₂); 4.52-4.16 (m, 2H, 1H of CH₂O+1H of CH₂O); 3.97-3.82 (m, 1H,CHO); 3.82-3.43 (m, 6H, 4H of 2×CH₂ piperazine+1H of CH₂O+1H of CHcyclopropane); 3.19-2.98 (m, 4H, 2×CH₂ piperazine); 1.53-1.00 (m, 4H,2×CH₂ cyclopropane)

MS (MeCN) 540 [M+1] 562 [M+23]

d) 2,3-dihydroxypropyl1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate

2,3-dihydroxypropyl7-(4-(benzyloxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(1.66 g, 3.1 mmol) was dissolved in ethanol (100 ml). Hydrogenation in aThales Nano H-Cube Hydrogenator (10% Pd/C cartridge, 11 bar) andevaporation of the organic solvent gave the crude product as a yellowsolid. Crystallisation from acetone gave the crude product as acolourless solid (0.71 g, 57%).

¹H-NMR (d₆-acetone), 500 MHz): δ[ppm]=8.72 (s, 1H, H-2); 7.91-7.80 (m,1H, H-5); 7.55-7.43 (m, 1H, H-8); 4.42-4.20 (m, 2H, 1H of CH₇O+1H ofCH₂O); 4.00-3.90 (m, 1H, CH); 3.82-3.75 (m, 1H, 1H of CH₂O); 3.70-3.5(m, 6H, 4H of 2×CH₂ piperazine+1H of CH₂O+1H CH of cyclopropane);3.15-3.02 (m, 4H, 2×CH₂ of piperazine); 1.48-1.30 (m, 2H, CH₂ ofcyclopropane); 1.25-1.10 (m, 2H, CH₂ of cyclopropane

MS (MeCN) 406 [M+1] 428 [M+23]

Example 6 2,3-dihydroxypropyl1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylatea)1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylicacid

1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylicacid (5.00 g, 15.10 mmol) was taken up in dioxane/water (1:1, 100 ml).1-iodopropane (3.08 g, 18.10 mmol), and sodiumhydrogencarbonate (3.81 g,45.30 mmol) was added and heated at 80° C. for 16 h. The crude reactionmixture was cooled to room temperature and acidified with 1M HCl to pH6. The reaction mixture was extracted with chloroform (3×100 ml), thecombined organic layer were dried over sodium sulfate and the volatileswere removed under reduced pressure yielding 3.87 g (69%) of pureproduct.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.77 (s, 1H, H-2); 8.07-7.97 (m, 1H,H-5); 7.41-7.30 (m, 1H, H-8); 3.57-3.46 (m, CH of cyclopropane ring);3.41-3.24 (m, 4H, 2×CH₂ of piperazine); 2.74-2.58 (m, 2×CH₂ ofpiperazine); 2.44-2.33 (m, 2H, CH₂N); 1.65-1.45 (m, 2H, CH₂); 1.45-1.28(m, 2H, CH₂ of cyclopropane ring); 1.28-1.12 (m, 2H, CH₂ of cyclopropanering); 0.94 (t, 3H, CH₃)

MS (CH₂Cl₂) 374 [M+1] 747 [2M+1]

b) (2,2-dimethyl-1,3-dioxolan-4-yl)methyl1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate

1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylicacid (8.86 g, 23.70 mmol) was dissolved in anhydrous dichloromethane(370 ml) under argon. 2,2-dimethyl-1,3-dioxolane-4-methanol (4.71 g,35.60 mmol), triethylamine (9.59 g, 94.80 mmol) and HBTU (9.90 g, 26.10mmol) were added and the reaction mixture was stirred at roomtemperature for three days (exclusion of light). The reaction mixturewas washed with saturated NaHCO₃ solution (500 ml), aqueous (pH 5)hydrochloric acid (500 ml) and water (500 ml) successively. The organiclayer was dried over Na₂SO₄ and the solvent was removed under reducedpressure, yielding 10.28 g (89%) of a yellow solid.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.53 (s, 1H, H-2); 8.09-7.95 (m, 1H,H-5); 7.32-7.17 (m, H-8); 4.51-4.41 (m, 1H, CH); 4.41-4.31 (m, 2H, 1H ofCH₂O+1H of CH₂O); 4.19-4.09 (m, 1H, CH₂O); 3.98-3.86 (m, 1H, CH₂O);3.50-3.36 (m, 1H of cyclopropane ring); 3.36-3.15 (m, 4H, 2×CH₂ ofpiperazine); 2.76-2.61 (m, 4H, 2×CH₂ of piperazine); 2.49-2.31 (m, 2H,CH₇N); 1.72-1.48 (m, 2H, CH₂CH₂CH₃); 1.44 (s, 3H, CH₃), 1.36 (s, 3H,CH₃); 1.33-1.25 (m, 2H, CH₂ of cyclopropane); 1.16-1.03 (m, 2H, CH₂ ofcyclopropane); 0.93 (t, 3H, CH₃)

c) 2,3-dihydroxypropyl1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate

(2,2-dimethyl-1,3-dioxolan-4-yl)methyl1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate(2.45 g, 5.03 mmol) was dissolved in anhydrous dichloromethane (245 ml)under argon. A 1 M solution of boron trichloride in dichloromethane (6.3ml, 6.30 mmol) was added dropwise and the reaction mixture was stirredat room temperature for 1 h. Methanol (25 ml) was added to the reactionmixture and the volatiles were removed under reduced pressure. The crudeproduct was purified through flash column chromatography (5% MeOH inCHCl₃) giving a yellow oil (1.58 g, 3.53 mmol, 70%).

MS (MeOH): 448.3 [M+1]

Levofloxacin(S)-(9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid Example 7 (3S) 2,3-dihydroxypropyl9-fluoro-3-methyl-10-(−4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylatea) (3S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl9-fluoro-3-methyl-10-(4-methylpipirazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

(3S)-(9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid (10.00 g, 27.7 mmol), was dissolved in CH₂Cl₂ (500 ml) under argon.2,2-dimethyl-1,3-dioxolane-4-methanol (5.49 g, 41.5 mmol) triethylamine(11.21 g, 110.8 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-trimethyluroniumhexafluorophosphate (11.56 g, 30.5 mmol) were added successively. Thereaction mixture was stirred under argon for 72 h. The reaction mixturewas washed with saturated NaHCO₃ solution (1×500 ml), water (1×50 ml)and dried over Na₂SO₄. The organic solvent was removed under reducedpressure giving a white solid. The crude product was crystallized fromacetonitrile giving the product in 44% yield (5.81 g).

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.29 (s, 1H, H-5); 7.65 (m, 1H, H-8);4.53-4.41 (m, 1H, CH); 4.41-4.25 (m, 5H, 1H of CH₂O, 1H of CH₂O, 2H ofCH₂O, 1H of CHN); 4.21-4.09 (m, 1H, 1H of CH₂O); 3.96-3.85 (m, 1H ofCH₂O); 3.43-3.23 (m, 4H, 2×CH₂ piperazine); 2.65-2.45 (m, 4H 2×CH₂piperazine); 2.36 (s, 3H, NCH₃); 1.58 (d, 3H, CH₃); 1.44 (s, 3H, CH₃),1.37 (s, 3H, CH₃).

MS (EtOH) 475 [M+1].

b)(S)-4-(6-((2,3-dihydroxypropoxy)carbonyl)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-10-yl)-1-methylpiperazin-1-ium2,2,2-trifluoroacetate

(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl9-fluoro-3-methyl-10-(4-methylpipirazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate(1.00 g, 2.1 mmol), was dissolved in CH₂Cl₂ (42 ml) under argon andcooled to 0° C. Trifluoroacetic acid (2.00 ml, 2.96 g, 26.0 mmol) wasadded and the reaction mixture was allowed to stir at 0° C. for 4 h andthen over night at room temperature. The reaction mixture was flushedthrough a plug of Al₂O₃ (10% MeOH in CHCl₃) (2×). After that the organicsolvents were collected and removed under reduced pressure giving theproduct as a yellow gum (0.24 g, 104%).

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.76 (s, H-5); 7.63-7.50 (m, H-8);4.74-4.61 (m, 1H, H-3 of benzoxazine ring); 4.61-4.50 (m, 1H, NHCHCH₂O); 4.50-4.33 (m, 2H, 1H of NHCHCH₂ O+1H of CH₂OCO); 4.33-4.24 (m, 1H,CH₂OCO); 4.03-3.93 (m, 1H, CHOH); 3.73-3.53 (m, 6H, 2×CH₂ piperazine+CH₂OH); 3.43-3.22 (m, 4H, 2×CH₂ piperazine); 3.01 (s, 3H, +NHCH₃ ); 1.55(d, 3H, CH₃).

MS (MeOH) 436 [M+1]; 458 [M+23]

c) (S)-2,3-dihydroxypropyl9-fluoro-3-methyl-10-(−4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

(S)-4-(6-((2,3-dihydroxypropoxy)carbonyl)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-10-yl)-1-methylpiperazin-1-ium2,2,2-trifluoroacetate (0.50 g, 0.91 mmol) was dissolved in methanolunder argon and cooled to 0° C. (ice/salt bath). 1 equiv. of NaOHdissolved in methanol (25 ml) was added slowly until the solutionreached pH 7-pH 8. The reaction mixture was passed through a plug ofAl₂O₃ (10% MeOH in CHCl₃). The organic solvent was removed under reducedpressure giving a yellow solid (0.35 g, 88%)

Or in an alternate procedure:

(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl9-fluoro-3-methyl-10-(4-methylpipirazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate(5.67 g, 10.8 mmol) was dissolved in 80% aqueous acetic acid (45 mL).The reaction mixture was heated at 75° C. for 8 hrs. The solvent wasremoved under reduced pressure. Toluene was added to the residue and thesolvent again removed under reduced pressure. The product was purifiedby column chromatography (10%, followed by 20%, 30%, and 75%methanol/chloroform as eluent) to give the title compound as anoff-white solid in 84% yield.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.67 (s, H-5); 7.56-7.40 (m, H-8);4.71-4.56 (m, 1H, H-3 of benzoxazine ring); 4.56-4.33 (m, 3H, 2H ofNHCHCH₂ O+1H of CH₂OCO); 4.33-4.21 (m, 1H, CH₇OCO); 4.02-3.91 (m, 1H,CHOH); 3.57-3.52 (m, 2H, CH₂ OH); 3.52-3.34 (m, 4H, 2×CH₂ piperazine);2.85-2.56 (m, 4H, 2×CH₂ piperazine); 2.43 (s, 3H, NHCH₃ ); 1.52 (d, 3H,CH₃).

MS (MeOH) 436 [M+1] 458 [M+23]

Example 8 (S)-1,3-dihydroxypropan-2-yl9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylatea) (S)-2-phenyl-1,3-dioxan-5-yl9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

(S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (4.18 g, 11.56 mmol) was dissolved inanhydrous dichloromethane (210 ml) under argon.1,3-O-benzylideneglycerol (2.50 g, 13.67 mmol), triethylamine (4.68 g,46.24 mmol) and HBTU (4.38 g, 11.56 mmol) were added successively. Thereaction mixture was stirred at room temperature (exclusion of light)for 3 days. The reaction mixture was washed with saturated NaHCO₃solution (500 ml), aqueous (pH 5) hydrochloric acid (500 ml) and water(500 ml) successively. The organic layer was dried over Na₂SO₄ and thesolvent was removed under reduced pressure. The crude product waspurified through flash column chromatography (SiO₂/10% MeOH in CHCl₃)yielding 4.32 g, 71%) of a yellow, crystalline solid.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.22 (s, 1H, H-5); 7.64-7.52 (m, 1H,H-8); 7.46-7.31 (m, 4H, ArH); 7.10 (d, 1H, ArH); 5.65 (s, 1H, CHOCO);4.91 (s, 1H, ArCH); 4.64-4.01 (m, 7H, 1H of CHN+2H of CH₂O+4H of2×CH₂O); 3.38-3.22 (m, 2×CH₂ of piperazine ring); 2.62-2.43 (m, 4H,2×CH₂ of piperazine ring); 2.36 (s, NCH₃); 0.95 (d, 3H, CHCH₃).

MS (MeOH) 524 [M+1] 546 [M+23]

b) (S)-1,3-dihydroxypropan-2-yl9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

(S)-2-phenyl-1,3-dioxan-5-yl9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate(0.50 g, 9.55 mmol), was dissolved in a mixture ofdichloromethane/methanol (2:1.5, 87.5 ml) under argon. Palladiumcatalyst (10 wt % Pd/C) (180 mg) was added, the flask was evacuated andallowed to stir 1 atm of hydrogen gas at room temperature for 16 hours.The crude reaction mixture was passed through a glass microfiber on asintered funnel. The volatiles were removed under reduced pressureyielding 370 mg (88%) of a yellow gum.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.72 (s, 1H), 7.57 (dd, 1H, J¹=12.6 Hz,J²=1.8 Hz), 4.67-4.60 (m, 1H), 4.55-4.49 (m, 1H), 4.41-4.35 (m, 2H),4.31-4.25 (m, 1H), 4.00-3.92 (m, 1H), 3.69-3.63 (m, 2H), 3.46-3.33 (m,4H), 2.71-2.60 (m, 4H), 2.40 (s, 3H), 1.53 (d, 3H, J=6.8 Hz).

Benzocaine (ethyl 4-aminobenzoate) Example 9 Ethyl4-((1,3-dihydroxypropan-2-yloxy)carbonylamino)benzoate a)2-phenyl-1,3-dioxan-5-yl carbonochloridate

Triphosgene (bis(trichloromethyl)carbonate (13.35 g, 45.0 mmol) wasadded under argon at room temperature to a solution of1,3-O-benzylideneglycerol (18.02 g, 100.0 mmol) in dry CH₂Cl₂ (300 ml).The reaction mixture was cooled to −40° C. and a solution of pyridine(10.9 ml, 135.0 mmol) was added over 35 min under stirring. Uponcompletion of the addition the reaction mixture was stirred for 30 minat −40° C. Then it was allowed to warm to 0° C. over 60 min andsubsequently warmed to rt over 3.5 h under stirring. The reactionproduct was used in the next step without any further purification

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=7.42-7.33 (m, 2H), 7.31-7.21 (m, 3H),5.50 (s, 1H), 4.72-4.70 (m, 1H), 4.34-4.28 (m, 2H), 4.18-4.09 (m, 2H)

b) Ethyl 4-((2-phenyl-1,3-dioxan-5-yloxy)carbonylamino)benzoate

Ethyl 4-aminobenzoate (benzocaine) (16.53 g, 0.10 mol) was dissolved indry CH₂Cl₂ (160 ml) under argon. The reaction mixture was cooled to 0°C. and triethylamine (16.7 ml, 0.12 mol) was added.2-phenyl-1,3-dioxan-5-yl carbonochloridate (224.27 g, 0.10 mol) (as asolution in 300 ml CH₂Cl₂—obtained in the previous reaction step) wasadded gradually over 40 min. The reaction mixture was stirred for 1 h at0° C. and then gradually warmed to room temperature and allowed to stirover night. The crude reaction mixture was washed with 1M aqueous HCl(2×300 ml), saturated NaHCO₃ solution (2×300 ml) and water (2×300 ml)successively. The organic layer was dried over Na₂SO₄ and the solventwas removed under reduced pressure. The crude product was purifiedthrough flash column chromatography (SiO₂/CHCl₃) yielding (25.9 g, 70.0mmol, 71%) of a colourless crystalline solid.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.00 (d, 2H, J=8.8 Hz), 7.55-7.50 (m,2H), 7.44 (d, 2H, J=8.8 Hz), 7.41-7.36 (m, 3H), 7.11 (s, 1H), 5.62 (s,1H), 4.41-4.33 (m, 4H), 4.25-4.22 (m, 2H), 1.38 (tr, 3H, J=7.1 Hz)

c) Ethyl 4-((1,3-dihydroxypropan-2-yloxy)carbonylamino)benzoate

Ethyl 4-((2-phenyl-1,3-dioxan-5-yloxy)carbonylamino)benzoate (4.70 g,12.7 mmol) was dissolved in ethanol (500 ml) under argon and Pd/C (2.48g, 2.3 mmol) was added. The flask was flushed with hydrogen and allowedto stir under 1 atm H₂ at room temperature for 16 h. The crude reactionmixture was passed through a plug of celite and the solvent was removedunder reduced pressure yielding (3.14 g, 11.2 mmol, 88%). The productwas used without any further purification.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.00 (d, 2H, J=8.8 Hz), 7.46 (d, 2H,J=8.8 Hz), 7.17 (s, 1H), 4.97-4.93 (m, 1H), 4.35 (quart, J=7.1 Hz),3.99-3.86 (m, 4H), 2.62-2.11 (br, 2H), 1.38 (tr, 3H, J=7.1 Hz)

Menthol (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol) Example 10(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2,3-dihydroxypropanoate a)Sodium (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate

Methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.00 g, 6.2mmol) was dissolved in 80% aqueous 1,4-dioxane. 1.2 M aqueous NaOHsolution was added (5.2 ml) and the reaction mixture was stirred at roomtemperature for 3 h. After that the solvents were removed under reducedpressure and a colourless solid was obtained (1.03 g, 6.1 mmol, 98%).The product was used immediately in the next reaction step withoutfurther purification.

b) (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid

Sodium (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.03 g, 6.1mmol) was dissolved in a mixture of water (1.2 ml) and ethyl acetate(1.2 ml) and cooled to 0° C. 2 M aqueous H₃PO₄ solution (7 ml) was addeduntil the reaction mixture reached pH 2. After that the reaction mixturewas saturated with NaCl and the reaction mixture was extracted withethyl acetate (3×20 ml). The organic layer was dried over Na₂SO₄ and thesolvent was removed under reduced pressure. The product (0.73 g, 4.9mmol, 81%) was used in the next step without any further purification.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=8.99-8.13 (br, 1H), 4.64-4.61 (m, 1H),4.32-4.25 (m, 1H), 4.22-4.17 (m, 1H), 1.52 (s, 3H), 1.41 (s, 3H)

c) (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl2,2-dimethyl-1,3-dioxolane-4-carboxylate

(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2.86 g, 19.6 mmol)was dissolved in anhydrous CH₂Cl₂ (120 ml) under argon. Menthol(1R,2S,5R)-2-isopropyl-5-methylcyclohexanol) (3.67 g, 23.5 mmol),triethylamine (7.93 g, 78.4 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-trimethyluronium hexafluorophosphate (8.18g, 21.6 mmol) were added successively. The reaction mixture was stirredunder argon for 72 h. The reaction mixture was washed with saturatedNaHCO₃ solution (3×50 ml), aqueous HCl (pH 5) (3×50 ml) and water (3×50ml) and dried over Na₂SO₄. The organic solvent was removed under reducedpressure, giving a yellow oil. (0.54 g, 0.93 mmol, 93%). The crudeproduct was purified through flash column chromatography (SiO₂/15%-25%graduent of ethyl acetate in hexane) yielding 3.16 (11.2 mmol, 57%) of ayellow oil.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=4.82-4.69 (m, 1H), 4.59-4.50 (m, 1H),4.25-4.18 (m, 1H), 4.10-4.01 (m, 1H), 2.03-1.94 (m, 1H), 1.89-1.77 (m,1H), 1.70-1.62 (m, 2H), 1.55-1.35 (m, 8H), 1.09-0.95 (m, 2H), 0.92-0.79(m, 7H), 0.74 (d, J=7.0 Hz)

d) (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2,3-dihydroxypropanoate

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.00 g, 35.2 mmol) wasdissolved in 98% aqueous ethanol (10 ml). Amberlyst 15 (wet) ionexchange resin (0.30 g) and bumping granulate were added. The reactionmixture was refluxed for 4 h without stirring (under argon). After that,the reaction was brought to room temperature, the resin and bumpinggranulate were removed and the solvent was removed under reducedpressure. The product was obtained in quantitative yield (0.94 g)

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=4.86-4.74 (m, 1H), 4.26-4.19 (m, 1H),3.92-3.87 (m, 1H), 3.85-3.79 (m, 1H), 3.25-3.14 (m, 1H), 2.22-2.08 (m,1H), 2.06-1.96 (m, 1H), 1.93-1.79 (m, 1H), 1.74-1.65 (m, 2H), 1.56-

Example 11 1,3-dihydroxypropan-2-yl(2S,5R)-2-isopropyl-5-methylcyclohexyl phosphonate a)Dichloro((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)phosphine

The phosphorus trichloride (56.0 ml, 87.89 g, 0.640 mol) was added todichloromethane (anhydrous) under argon gas to obtain a solution. Thesolution was cooled to −30° C. and (−)-menthol (1R,2S,5R) (10.00 g,0.0640 mol) was added portion wise over 10 mins. The solution wasallowed to warm to ambient temperature and was allowed to stir atambient temperature for 16 hours. The solvent was removed in vacuo toobtain a colourless oil (16.46 g). The crude product was used directlyin the subsequent step.

b) (2S,5R)-2-isopropyl-5-methylcyclohexyl 2-phenyl-1,3-dioxan-5-ylphosphonate

The dichloro(2S,5R)-2-isopropyl-5-methylcyclohexyloxyphosphine (8.23 g,0.0320 mol) was dissolved in dichloromethane (anhydrous) (100 ml) underargon gas. Cooled to 0° C. Added a solution ofcis-1,3-benzylideneglycerol (7.21 g, 0.0400 mol) and tert-butanol (2.97g, 0.040 mol) (1:1) in dichloromethane (anhydrous) dropwise over 30mins. Then added triethylamine (8.9 ml, 6.47 g, 0.0640 mol) dropwise.Allowed to stir at 0° C. for 10 mins. And then allowed to gradually warmto ambient temperature. And removed solvent in vacuo to obtain acolourless crystalline solid (26.67 g).

The crude product was chromatographed on silica gel using EtOc/petspirit 60-80 to obtain the product fraction as a colourless oil (1.29 g)

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=7.93-7.92 (m, 0.5H, P—H), 7.58-7.29 (m,5H), 6.17-6.16 (m, 0.5H, P—H), 5.56 (s, 1H), 4.53-3.98 (m, 6H),2.31-1.89 (m, 3H), 1.88-0.57 (m, 15H)

c) 1,3-dihydroxypropan-2-yl (2S,5R)-2-isopropyl-5-methylcyclohexylphosphonate

Thedichloro(2S,5R)-2-isopropyl-5-methylcyclohexyl-2-phenyl-1,3-dioxan-5-ylphosphonate (0.97 g; 2.54 mmol) was dissolved in 80% (v/v) aqueousacetic acid (10 ml) and allowed to stir at 70° C. for 3 hrs. The solventwas removed in vacuo followed by pumping under high vacuum to obtain anoil (0.69 g, 2.37 mmol).

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=7.89-7.87 (m, 0.5H, P—H), 6.01-5.89 (m,0.5H, P—H), 4.42-3.28 (m, 8H), 2.29-0.51 (m, 18H)

Phenol

Example 12 1,3-dihydroxypropan-2-yl phenyl succinate a)4-oxo-4-phenoxybutanoic acid

Phenol (1.88 g, 20.0 mmol) was dissolved in a solution of sodiumcarbonate (anhydrous) (1.06 g, 10.0 mmol) in water (20 ml) and cooled to0° C. Succinic anhydride (2.00 g, 20.0 mmol) was added and thesuspension was allowed to stir at 0° C. for 1 h. The reaction mixturewas gradually warmed to room temperature and stirred over night. Theclear solution was cooled to 0° C. and acidified to pH 0 (addition of 1Maqueous HCl). The reaction mixture was extracted with chloroform (3×25ml), dried over Na₂SO₄, filtered and the solvent removed under reducedpressure to obtain a white solid (1.63 g, 8.4 mmol, 42%). The productwas used without any further purification.

¹H-NMR (CDCl₃, 200 MHz): δ[ppm]=7.44-7.03 (m, 5H), 2.95-2.77 (m, 4H)

b) Phenyl 2-phenyl-1,3-dioxan-5-yl succinate

4-oxo-4-phenoxybutanoic acid (1.00 g, 5.15 mmol) was dissolved inanhydrous CH₂Cl₂ (55 ml) under argon. Menthol 1,3-O-benzylideneglycerol(1.11 g, 6.18 mmol), triethylamine (2.09 g, 20.6 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-trimethyluronium hexafluorophosphate (2.15g, 5.67 mmol) were added successively. The reaction mixture was stirredunder argon for 72 h. The reaction mixture was washed with saturatedNaHCO₃ solution (3×50 ml), aqueous HCl (pH 5) (3×50 ml) and water (3×50ml) and dried over Na₂SO₄. The organic solvent was removed under reducedpressure, giving a yellow oil. (0.54 g, 0.93 mmol, 93%). The crudeproduct was purified through flash column chromatography (SiO₂/10% MeOHin chloroform) yielding 0.98 g (2.58 mmol, 50%) of a yellow solid.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=7.54-7.48 (m, 2H), 7.41-7.31 (m, 5H),7.23-7.19 (m, 1H), 7.13-7.06 (m, 2H), 5.57 (s, 1H), 4.78 (m, 1H),4.33-4.29 (m, 2H), 4.20-4.16 (m, 2H), 2.97-2.86 (m, 4H)

c) 1,3-dihydroxypropan-2-yl phenyl succinate

Phenyl 2-phenyl-1,3-dioxan-5-yl succinate (0.11 g, 0.3 mmol) wasdissolved in ethanol (20 ml) under argon and Pd/C (0.09 g, 0.1 mmol) wasadded. The flask was flushed with hydrogen and allowed to stir under 1atm H₂ at room temperature for 16 h. The crude reaction mixture waspassed through a plug of celite and the solvent was removed underreduced pressure yielding (0.9 g, 0.26 mmol, 89%). The product was usedwithout any further purification.

¹H-NMR (CDCl₃, 400 MHz): δ[ppm]=7.43-7.33 (m, 2H), 7.25-7.21 (m, 1H),7.12-7.05 (m, 2H), 4.97 (quint, 1H, J=4.4 Hz), 3.88-3.80 (m, 4H),2.95-2.91 (m, 2H), 2.82-2.75 (m, 2H), 2.58-1.60 (br, 2H)

(6) Synthesis of the Protected Monoglyceride—Linker-Building Blocks

(a) Synthesis of Protected Monoglycerides with a Diacid Linker

1,3-Benzylideneglycerol and solketal((2,2-dimethyl-1,3-dioxolan-4-yl)methanol) are each separately dissolvedin organic solvent and each reacted with a diacid (succinic, glutaric,adipic, pimelic, suberic, azelaic, sebacic) under appropriateconditions.

(b) Synthesis of Protected Monoglycerides with an Omega Hydroxy AcidLinker

1,3-Benzylideneglycerol and solketal are each separately dissolved inorganic solvent and each reacted with an omega hydroxy acid underappropriate conditions.

(c) Synthesis of Protected Monoglycerides with a Chloroformate Linker

1,3-Benzylideneglycerol and solketal are each separately dissolved inorganic solvent and each reacted with an omega hydroxy acid underappropriate conditions. The product of this conversion is reacted withtriphosgene to give the protected monoglycerides with a chloroformatelinker.

(d) Synthesis of Chloroformate Functionalised Protected Monoglycerides

1,3-Benzylideneglycerol and solketal are each separately dissolved inorganic solvent and each reacted with triphosgene under appropriateconditions.

(7) Synthesis of the Monoglyceride-Linker-Bioactive Agent-Conjugates

(a) Coupling of Hydroxy Containing Bioactive Agents with ProtectedMonoglycerides with a Diacid Linker

A hydroxy containing bioactive agent—such as Codeine, Fluconazole,Latanoprost or Dexamethasone—(after conversion into a prodrug byprotecting additional functional groups with appropriate bioerodableprotection groups) is reacted with protected monoglycerides with adiacid linker. The monoglyceride protection groups are removed underappropriate conditions giving the monoglyceride functionalised (at theprimary or secondary alcohol positions of the glyceride) bioactive agentmonomers.

(b) Coupling of Hydroxy Containing Bioactive Agents with ProtectedMonoglycerides with An Omega Hydroxy Acid Linker

A carboxy acid containing bioactive agent—such as Ciprofloxacin,Levofloxacin or Valproic acid—(after conversion into a prodrug byprotecting additional functional groups with appropriate bioerodableprotection groups) is reacted with protected monoglycerides with a omegahydroxy acid linker. The monoglyceride protection groups are removedunder appropriate conditions giving the monoglyceride functionalised (atthe primary or secondary alcohol positions of the glyceride) bioactiveagent monomers.

(c) Coupling of Amine Containing Bioactive Agents with ProtectedMonoglycerides with a Chloroformate Linker

An amine containing bioactive agent—such as Benzocaine—(after conversioninto a prodrug by protecting additional functional groups withappropriate bioerodable protection groups) is reacted with protectedmonoglycerides with a chloroformate linker. The monoglyceride protectiongroups are removed under appropriate conditions giving the monoglyceridefunctionalised (at the primary or secondary alcohol positions of theglyceride) bioactive agent monomers.

(d) Coupling of Amine Containing Bioactive Agents with ChloroformateFunctionalised Protected Monoglycerides

An amine containing bioactive agent—such as Benzocaine—(after conversioninto a prodrug by protecting additional functional groups withappropriate bioerodable protection groups) is reacted with chloroformatefunctionalised protected monoglycerides. The monoglyceride protectiongroups are removed under appropriate conditions giving the monoglyceridefunctionalised (at the primary or secondary alcohol positions of theglyceride) bioactive agent monomers.

(e) Coupling of Amine Containing Bioactive Agent with Carboxylic AcidFunctionalised Protected Monoglyceride

An amine containing bioactive agent—such as Benzocaine—(after conversioninto a prodrug by protecting additional functional groups withappropriate bioerodable protection groups) is converted into thecorresponding isocyanate. Reaction of the isocyanate with a carboxylicacid functionalised protected monoglyceride produces (via release ofCO₂) the corresponding amide derivative which is subsequentlydeprotected.

f) Conversion of an Amine Containing Bioactive Agent to an AromaticCarbamate Containing Functionalised Protected Monoglyceride

An amine containing bioactive agent—after conversion into a prodrug byprotecting additional functional groups with appropriate bioerodableprotection groups—is converted into the corresponding functionalisedprotected monoglyceride containing an aromatic carbamate.

(8) Synthesis of Bioactive Agent-Linker Conjugates

(a) Synthesis of Diacid-Bioactive Agent Conjugates

A hydroxy containing bioactive agent—such as Codeine, Fluconazole,Latanoprost or Dexamethasone—(after conversion into a prodrug byprotecting additional functional groups with appropriate bioerodableprotection groups) is reacted with a diacid or a diacid derivative.

(b) Synthesis of Acid/Omega Hydroxy-Bioactive Agent Conjugates

An carboxy acid containing bioactive agent—such as Ciprofloxacin,Levofloxacin or Valproic acid—(after conversion into a prodrug byprotecting additional functional groups with appropriate bioerodableprotection groups) is reacted with an acid/omega hydroxy linker or aderivative thereof.

(c) Synthesis of an Acid/Chloroformate-Bioactive Agent Conjugates

An amine containing bioactive agent—such as Benzocaine—(after conversioninto a prodrug by protecting additional functional groups withappropriate bioerodable protection groups) is reacted with a anacid/chloroformate linker or a derivative thereof.

d) Conversion of an Carboxy Acid Containing Bioactive Agent toFunctionalised Protected Monoglyceride Containing a Spacer Group.

An carboxy acid containing bioactive agent—after conversion into aprodrug by protecting additional functional groups with appropriatebioerodable protection groups—is converted into the correspondingfunctionalised protected monoglyceride with a spacer group that can bemodified to meet the required polymer properties and release kinetics.

e) Conversion of an Alcohol Containing Bioactive Agent to FunctionalisedProtected Monoglyceride Containing a Spacer Group.

An alcohol containing bioactive agent—after conversion into a prodrug byprotecting additional functional groups with appropriate bioerodableprotection groups—is converted into the corresponding functionalisedprotected monoglyceride with a spacer group that can be modified to meetthe required polymer properties and release kinetics.

(9) Synthesis of Monoglyceride-Linker-Bioactive Agent-Conjugates

(a) Coupling of Diacid-Bioactive Agent Conjugates with ProtectedMonoglycerides

A diacid-bioactive agent conjugate, containing a bioactive agent such asCodeine, Fluconazole, Latanoprost or Dexamethasone—(after conversioninto a prodrug by protecting additional functional groups withappropriate bioerodable protection groups) is reacted with protectedmonoglycerides. The monoglyceride protection groups are removed underappropriate conditions giving the monoglyceride functionalised (at theprimary or secondary alcohol positions of the glyceride) bioactive agentmonomers.

(b) Coupling of an Omega Hydroxy Acid-Bioactive Agent Conjugate withProtected Monoglycerides

An omega hydroxy acid-bioactive agent conjugate containing a bioactiveagent—such as Ciprofloxacin, Levofloxacin or Valproic acid—(afterconversion into a prodrug by protecting additional functional groupswith appropriate bioerodable protection groups) is reacted withprotected monoglycerides. The monoglyceride protection groups areremoved under appropriate conditions giving the monoglyceridefunctionalised (at the primary or secondary alcohol positions of theglyceride) bioactive agent monomers.

(c) Coupling of an Acid/Chloroformate-Bioactive Agent Conjugates withProtected Monoglycerides

An acid/chloroformate-bioactive agent conjugate containing a bioactiveagent—such as Benzocaine—(after conversion into a prodrug by protectingadditional functional groups with appropriate bioerodable protectiongroups) is reacted with protected monoglycerides. The monoglycerideprotection groups are removed under appropriate conditions giving themonoglyceride functionalised (at the primary or secondary alcoholpositions of the glyceride) bioactive agent monomers.

Conversion of a phosphate containing bioactive agent to functionalisedprotected monoglyceride (as phosphate ester) with and/or without aspacer group.

X=spacer—as described in the previous text, R=protection group

A phosphate containing bioactive agent—after conversion into a prodrugby protecting additional functional groups with appropriate bioerodableprotection groups—is converted into the corresponding functionalisedprotected monoglyceride (as phosphate ester) with or without a spacergroup that can be modified to meet the required polymer properties andrelease kinetics.

Polymer Production

This section describes how the functionalised bioactive-monomersconjugates have been covalently linked to the polymer backbone andformed part of the bioactive-polymer conjugates containing the selectedbioactive as a pendant attachment. The pendant attached bioactive isable to be released by the breakdown of the covalent bonds throughhydrolysis and the degradation of the linkages attaching the bioactiveto the polymer.

Synthesis of Polyols

(a) DLLA 1000

To a stirred suspension of DL-Lactic acid (20 mL, 268.3 mmol) and1,4-butane diol (1.647 mL, 18.6 mmol), tin (II)-2-ethyl hexanoate (2drops, 0.059 mmol) was added. The reaction was heated at 140° C. undervacuum for 3 days. The resulting pale yellow oil crude material wasobtained as the title compound and used without further purification.The molecular weight was determined by GPC using the methods outlinedabove.

MW: 876.5.

In an alternative procedure, DL-Lactic acid (0.5002 g, 3.47 mmol) wasadded to a Schlenk flask and anhydrous toluene (1.0 ml) was added. Themixture was agitated to aid dissolution and 2,2′-dithioethanol (0.07 g,0.591 mmol) tin (II)-2-ethyl hexanoate (0.022 g, 0.069 mmol) were added.The vessel was sealed and stirred at 110° C. for 17.5 hrs. The reactionwas cooled and added to 15 ml of hexane and transferred to a centrifugetube using a small quantity of THF. The mixture was centrifuged, solventdecanted, further hexane added and centrifuged for 5 minutes. Thesolvent was decanted and the product was dried under high vacuum. Themolecular weight was determined by GPC using the methods outlined above.

MW: 1098.53

Polyurethane and Polyester-Urethane Formulations

Polylactic Acid (Mw 1000 g/mol) and polycaprolactone diol (Mw 1000g/mol) were both dried under high vacuum overnight at 75° C. before use.Hexamethylene diisocyanate (HDI) and Ethyl-lysine diidocyanate (ELDI)were distilled before use.

Polyurethane Bulk Synthesis Method

The required amounts of DLLA, PLGA or PCLD (ERA Chemicals Pty Ltd)polyester polyols were weighed into a beaker and kept warmed in apre-heated nitrogen purged oven. The required amount ofbioactive-monomer conjugate was first dried under vacuum with mild heatthen mix added to the reaction beaker containing the DLLA, PLGA or PCLDcomponents and returned to an oven to equilibrate.

The required amount of diisocyanate HDI was weighed into a syringe foraddition to the other components. Three drops of Dibutyltin Dilaurate(DBTDL) or 2 Ethyl Hexanoate ((Sn2EH) catalyst were first added to thebioactive-monomer conjugate and/polyol mixture. The monomer/s andcatalyst were mixed well before either the HDI or ELDI was added via asyringe. The whole mixture was mixed and stirred vigorously with aspatula until the mixture thickened considerably before it was pouredonto a baking tray. The tray was then placed in an oven overnight at 80°C. to cure the polymer.

Optimisation of the molecular weight was achieved by varying the HDI orELDI index. The molecular weights of the polymers were characterised byGel Permeation Chromatography (GPC) using THF or DMF as the solvent.Reaction completion and structural integrity were confirmed by means of¹H NMR.

Polyurethane Solution Synthesis Method

Bioactive-monomer conjugates were dried under vacuum with mild heat thenadded to dry DMF (typically >1 g) in a small round bottle flask. Twodrops of DBTDL or Sn2EH were added and the mixture warmed in an oil bathat 85° C. before injecting in a slight excess of HDI or ELDI. Themixture was typically found to have thickened considerably afterstirring overnight at 85° C. The DMF solvent was removed and thematerial was then analysed or further purified.

Polyurethane Precipitation Purification Method

The resulting PU was dried to remove any DMF present. The polymer wasthen dissolved in a minimal amount of DMSO then precipitated fromsolution into acetonitrile. Any unreacted bioactive-monomer conjugateremained dissolved in the DMF/Acetonitrile solution.

Aliphatic Polyurethanes containing Valproic Acid Monoglyceride (VA-MG)

Comparative Example 1 PU Polymer Bioactive-Conjugate Containing 50 Mole% VA-MG

A polymer-bioactive conjugate containing 50 mole % VA-MG was formed bythe reaction of 1:1 molar ratio of VA-MG and HDI according to thePolyurethane Bulk Synthesis Method. The VA-MG synthesised in Example 1above was dried under vacuum. The VA-MG (1.005 g, 4.6 mmol) was added toa dried 150 ml polypropylene (PP) beaker. DBTDL (dibutyl tin dilaurate)catalyst was added to the beaker (0.0041 g). The mixture was stirred andheated in the beaker at 70° C. for 5 mins. HDI was then added by syringe(1.003 g 5.9 mmol) with stirring. The mixture was then poured into aTeflon coated tray and allowed to cure for 4 hours in an oven at 70° C.Films of the polymer were pressed using a melt press set at 90° C.Teflon coated metal press plates were used. The thickness was controlledusing a 200 micron shim plate. The sample was pressed for 5 mins at 90°C. and then cooled to room temperature using tap water (flowing throughthe press platterns).

The polymer film was found to be clear, flexible and tough. The nominalloading the valproic acid in the polymer is approximately 30 wt %.

Example 13 Flexible PU Polymer Bioactive-Conjugate Containing 33 Mole %VA-MG

A polymer-bioactive conjugate containing 33 mole % VA-MG was formed bythe reaction of VA-MG, PCLD1000 and HDI according Polyurethane BulkSynthesis Method in the proportions 34 mole %, 15 mole % and 51 mole %,respectively. PCLD 1000 (2.508 g, 2.524 mmol) and VA-MG (1.185 g, 5.428mmol) were added to a dried glass beaker and mixed thoroughly with aspatula. Three drops of DBTDL (dibutyltin dilaurate) catalyst was thenadded to the polyols mixture. HDI (1.393 g, 8.281 mmol) was delivered bya syringe and vigorous mixing was applied. The hot mixture was thenpoured onto a Teflon coated tray and placed in an oven to cure overnightat 85° C. Through isocyanate index optimisation, polyurethanes of highmolecular weights and strength were synthesised from this formulation. A250 micron thick film prepared by the process described above was clear,tough. The loading of VA-MG achieved by this formulation isapproximately 23.3 wt %.

Aliphatic Polyurethanes Containing Levofloxacin Monoglyceride (LVX-MG)

Example 20 Polyurethane Bioactive-Polymer Conjugate Containing >50 wt %LVX-MG

LVFX-MG (0.20 g, 0.457 mmol) was dissolved in 2.5 ml of dry DMF solvent.Two drops of the DBTDL catalyst was added to the solution and heated to65° C. in a small round bottle flask with a rubber seal. HDI (0.078 g,0.464 mmol) added via a micro syringe and allowed to react overnight.After removing the DMF, flaky but brittle solid was produced. Afterprecipitation in acetonitrile solvent, a whitish material was collected.

Example 22 Polyurethane Bioactive-Polymer Conjugate Containing 13 Wt %Bound LVX (as LVX-MG)

DLLA (1.35 g, 1.20 mmol), PCLD (0.38 g, 0.384 mmol) and 3 drops of DBTDLwas mixed in a beaker and warmed in an oil bath at 65° C. LVFX-MG (0.65g, 1.04 mmol) was dissolved in 3 ml of dry DMF solvent. The two mixtureswere then combined before injecting in the HDI (0.52 g, 3.09 mmol). Overthe course of a few hours, the mixture's viscosity has increasedconsiderably. Transferred the material into a crucible and heated in anoven at 80° C. overnight. After removing the solvent, a sticky waxymaterial was produced.

TABLE 2 Bioactive-Polyurethane- Conjugates andBioactive-Polyester-Urethane Conjugates Relevant Bioactive MonomerConjugate Example No PCLD DLLA PLGA 50:50 and weight 1000 1000 1000 HDIELDI Catalyst Example (g) (g) (g) (g) (g) (g) (drops) Method CommentsCE-1 Ex1 0 0 0 1.0037 0 5 DBTDL Bulk Mn = 9,575 1.0053 Mw = 15,332 Mp =15,205 PD = 1.60 Clear hard polymer 13 Ex1 2.5086 0 0 1.3900 0 3 DBTDLBulk Mw 254,869; 1.1800 Mn 127,312. Clear flexible film 14 Ex2 2.7382 00 1.3108 0 5 DBTDL Solution Sticky Clear film 1.426 15 Ex2 1.6205 0 00.7713 0 3 DBTDL Solution Rubbery polymer 0.8500 16 Ex3 0 0 0 1.0855 0 5DBTDL Bulk Rubbery polymer 3.0358 17 Ex3 2.5071 0 0 0.9844 0 5 DBTDLBulk Rubbery flexible 1.5860 polymer 18 Ex3 2.5185 0 0 0.9762 0 5 DBTDLBulk Flexible polymer 1.5342 19 Ex7 0 0 0 0.1652 0 5 DBTDL Bulk StiffPolymer 0.4161 LVX-ME * 0.1869 20 Ex7 0 0 0 0.078 0 2 DBTDL SolutionFlaky brittle 0.2 polymer 21 Ex7 0 0 0 0.075 0 2 DBTDL Solution Stiffpolymer 0.2136 ppt Acetonitrile LVX-ME * 0.1223 22 Ex7 0.38 1.35 0 0.520 3 DBTDL Solution Sticky waxy 0.4511 polymer LVX-ME * 0.1989 23 Ex7 0 00 0.2733 0 5 DBTDL Solution Stiff polymer 0.7043 ppt AcetonitrileLVX-ME * 0.3018 24 Ex8 0 0 0 0.2002 0 3 DBTDL Solution Stiff Polymer0.5088 25 Ex8 4.9999 0 0 2.0001 0 3 DBTDL Solution Flexible polymer3.022 26 Ex8 0 0 1.5018 0.6162 0 5 DBTDL Solution Brittle and hard0.8879 polymer 27 Ex8 1.5140 0 0 0 0.7623 5 DBTDL Solution Soft and waxy0.7623 polymer 28 Ex8 0.5186 2.1986 0 0.6169 0 5 DBTDL Solution stiffpolymer 0.6034 29 Ex9 1.2702 0 0 0.5971 0 5 DBTDL Solution Flexiblewhite 0.6529 polymer Mn = 11,979 Mw = 22,898 Pd = 1.91 30 Ex9 1.2499 0 00 0.7121 5 DBTDL Solution Flexible white 0.5379 polymer Mn = 14,222 Mw =28,259 Pd = 1.98 31 Ex10 1.7380 0 0 0.8928 0 5 DBTDL Solution Flexiblepolymer 0.86 32 Ex11 0 0 0 0.5839 4 Sn2EH Bulk Yellow sticky 0.70 gflexible polymer 33 Ex12 3.6861 0 0 1.8119 0 5 DBTDL Solution Flexiblepolymer 1.9000 34 Ex1 2.4988 0 0 1.1624 0 10 DBTDL Solution Toughflexible 0.3184 polymer Ex8 0.6328 Ex9 0.4106 35 Ex1 0.6780 0 0 0.31 0 5DBTDL Solution Tough flexible 0.1343 polymer Ex8 0.2437

Example 36 Blends of Precipitated PU Bioactive-Polymer ConjugateContaining >50 Wt % LVX-MG with Amorphous PU

It was found that polymer produced by selective precipitation was toobrittle to melt press. It was decided to melt blend these materials withthe amorphous PU's produced for the earlier Levoflocaxin/amorphous PUblend work.

Film samples of the melt blend of the LVX-MG bioactive polymer conjugate(Example 15) with amorphous PU have been produced which contain 10 wt %LVX.

Example 37 Polyurethane Bioactive-Polymer Conjugate ContainingLevofloxacin Monoglyceride

Levofloxacin monoglyceride (1.5002 g, 3.4 mmol), DBTDL (0.021 g, 0.03mmol), ELDI (0.7860 g, 3.5 mmol) and PCLD (0.7639 g, 0.7 mmol) in DMF(10 mL) in a Schlenk flask were heated at 80° C. for 24 hours. Aftercooling the polymer was precipitated by the slow addition to 20 timesits volume of diethyl ether. The mixture was centrifuged and thesupernatant solvent decanted to give the crude product which wasdissolved in the minimum amount of DCM and added to ten times thatvolume of diethyl ether, centrifuged and the supernatant decanted. Thisprocess was repeated once more to isolate the product which was driedovernight under high vacuum to give 1.656 g of polymer product. Themolecular weight was determined by GPC using the methods outlined above.

MW: 29,080.

Example 38 Polyurethane Bioactive-Polymer Conjugate ContainingLevofloxacin Monoglyceride

Levofloxacin monoglyceride (2.01 g, 4.615 mmol), DBTDL (0.0289 g, 0.0459mmol) and ELDI (1.059 g, 4.68 mmol) in DMF (10 mL) was heated at 80° C.for 24 hours. 100 mL of diethyl ether was placed in a centrifuge tubeand to it the cooled reaction mixture was added dropwise with stirring.A white solid separates which clumps together towards the end giving abuff coloured paste. The mixture was centrifuged and the solventdecanted.

The paste was stirred with diethyl ether (50 mL) until the solidseparates out and then centrifuged and the solvent decanted. Thisprocess was repeated once more and the product was isolated and driedunder high vacuum to give the product as 2.409 g of a buff colouredsolid. The molecular weight was determined by GPC using the methodsoutlined above.

MW: 40,890

Polyesters

Reaction of VA-MG with Di-Acids or Anhydrides

VA-MG was dried under high vacuum with magnetic stirring at roomtemperature in the flasks used for conducting the reaction. Thereactions was carried out at 110° C. in 50 mL round bottom flasks fittedwith magnetic stirrer bar, a 10 mL capacity Dean and Stark trap and areflux condenser in the presence of a condensation catalyst (DBTDL). Theapparatus were blanketed with nitrogen to prevent moisture ingress.

Toluene distilled from sodium was used as a solvent for the reaction.The collection arm of the Dean and Stark trap was filled with driedmolecular sieve (4A) to further promote the removal of water from thereaction mixture

Reaction work-up involved the removal of the toluene by rotovap and highvacuum. All samples were washed with 0.1M HCl then water and dried underhigh vacuum. Reaction completion and structural integrity was confirmedby ¹H NMR and molecular weights determined by GPC.

Reaction of VA-MG with Acid Chlorides

VA-MG was dried under high vacuum with magnetic stirring at roomtemperature in the flasks used for conducting the reaction.

The acid chlorides were distilled under vacuum and stored under nitrogenin a freezer before use. DCM was dried over molecular sieve using asolvent delivery system (SDS).

Reactions were carried out in DCM within a 50 mL round bottom flaskfitted with magnetic stirrer bar and a reflux condenser. The flasks wereblanketed with nitrogen to prevent moisture ingress.

Triethylamine (TEA) was added to the reaction flask in 20% excess todrive the reaction by promoting the formation of the acid chloride salt.The TEA was dried by distillation off calcium hydride under a nitrogenblanket.

Reaction work-up involved washing of the TEA-HCl salt in 0.1M HCL andwater, drying the organic layer over anhydrous sodium sulphate,filtering and removal of the DCM by rotovap. All samples were washedwith 0.1M HCL then water and dried under high vacuum. Reactioncompletion and structural integrity was confirmed by ¹H NMR andmolecular weights determined by GPC.

TABLE 3 Bioactive-Polyester- Conjugates Produced by Polycondensation ofDiAcids or Anhydrides with Bioactive Monomer Conjugate's BioactiveMonomer Conjugate Example No and weight Succinic Anhydride Succinic AcidAdipic Acid Sebacic Acid Catalyst ID (g) (g) (g) (g) (g) Solvent (drops)Comments Ex39 Ex1 1.4531 0 0 Toluene 10 DBTDL Waxy polymer 3.0089 Ex40Ex1 0 0 1.3494 Toluene 10 DBTDL Waxy polymer 2.000 g Ex41 Ex1 2.7382 0 01.8522 Toluene 10 DBTDL Waxy polymer 2.0059 Ex42 Ex8 0.1154 0 0 0Toluene 10 Sn2EH Waxy polymer 0.5022 Ex43 Ex8 0 0.1343 0 0 Toluene 10Sn2EH Dark Waxy Polymer 0.4807 Ex44 Ex8 0 0 0.1671 0 DMF 10 DBTDLYellow/Brown Wax 0.4951 Ex45 Ex8 0 0 0 0.0.2326 DMF 10 Sn2EH Dark WaxyPolymer 0.4991

TABLE 4 Bioactive-Polyester- Conjugates Produced by Reaction of DiAcidChlorides with Bioactive Monomer Conjugate's Bioactive Monomer ConjugateAdipoyl Sebacoyl Example No and weight Succinoyl Chloride ChlorideChloride TEA Mn ID (g) (g) (g) (g) Solvent (Weight) Mw Comments Ex46 Ex10 0 1.3694 DCM 1.39 g Mn = 1647 Wax 1.2549 Mw = 6190 Ex47 Ex1 0 1.7289 0DCM 1.905 Mn = 557 Yellow Liquid 1.3173 Mw = 787 Ex48 Ex1 0 0 2.28231.921 Mn = 2724 Yellow Wax 1.2008 Mw = 7016 Ex49 Ex1 0 1.7397 0 3.51 Mn= 619 Yellow Liquid 2.0688 Mw = 994 Ex50 Ex1 0 0 2.207 2.795 Mn = 2137Yellow Wax 2.0134 Mw = 7727

Example 51 Polymer Erosion

The extent of polymer erosion was determined gravimetrically. Sampleswere weighed prior to and at the end of each erosion experiment. Sampleswere incubated in isotonic phosphate buffer (IPB), adjusted to pH 7.4using orthophosphoric acid and containing 0.01% sodium azide as apreservative, and incubated at 37° C. with continuous stirring for thedesired period of incubation. At the end of the incubation periodsamples were washed with distilled water and dried to constant weight.

Drug Release

Following in vitro release guidelines recommended by the InternationalOrganisation of Standardisation⁹, polymer-coated discs or cylindricalsamples were suspended in wire baskets which were immersed in isotonicphosphate buffer (IPB), adjusted to pH 7.4 using orthophosphoric acidand containing 0.01% sodium azide as a preservative, and incubated at37° C. with continuous stirring. Aliquots of the receptor solution wereremoved for analysis at predetermined time points until the release fromthe polymer no longer increased.

The amount of drug released from the polymer-coated discs at the varioustime points was quantified by reserve phase high performance liquidchromatography (HPLC) with a UV absorbance detector (levofloxacin) andrefractive index (valproic acid) and drug separation was performed on aC18 column. Levofloxacin and Valproic Acid were eluted isocraticallyusing a degassed mobile phase.

In Vitro Assessment of Antimicrobial Activity

The antimicrobial activity of polymer-coated discs was assessed usingthe disc diffusion test based on protocols recommended by the Clinicaland Laboratory Standards Institute¹⁰. Colonies selected from anovernight culture of S. aureus ATCC strain 29213 were suspended inphosphate-buffered saline (PBS) at a density of 1.5×10⁸ CFU/ml. Thesuspension was then used to inoculate the surface of a Mueller-Hintonagar plate. Discs coated on one side only were placed coated-side-downonto the freshly inoculated agar and the plates were incubated at 37° C.in air for 18 hr. Growth inhibition was inspected visually the followingday. Discs were then transferred to freshly inoculated agar plates eachday until no inhibition of growth occurred.

Example 52 Release of Levofloxacin

The following charts show the release of levofloxacin from the polymersystems described in Examples 20, 25, 26, 28, 27, and 36. The amount oflevofloxacin was determined by HPLC as previously described at the timeintervals given in the chart. FIG. 2 shows the release of bothlevofloxacin (LVX) and the levofloxacin incorporating monomer,levofloxacin monoglyceride (LVX-MG), from the polymer described inExample 20. The data shows that levofloxacin is released from thepolymer as the free active drug with very little released as theinactive levofloxacin-monoglyceride. FIG. 3 shows the release oflevofloxacin from a number of different polymers described in Examples25, 26, 27 and 28. The data shows levofloxacin is released from each ofthe polymers 25, 26, 27 and 28. FIG. 4 shows an in vitro assessment ofantimicrobial activity from polymers described in Examples 20 and 36.Antimicrobial activity is demonstrated in both polymers.

The polymer system of Example 37 was used to form cylinders of constantlength and different diameter (0.5 mm, 0.7 mm, 1.0 mm and 1.5 mm). Thecumulative release of levofloxacin from the cylinders over a period of120 days was determined by HPLC and is shown in FIG. 5. FIG. 6 shows thepercentage of levofloxacin released from the polymer conjugate over timefor each sample. The amount of levofloxacin released per 24 hour periodduring the study is shown in FIG. 7.

Example 53 Release of Valproic Acid

The following charts show the release of Valproic Acid from the polymersdescribed in examples CE1, 14, 16 and 17. The amount of Valproic Acidwas determined by HPLC as previously described at the time intervalsgiven in the chart. FIG. 8 shows the release of Valproic Acid from thepolymers described in examples CE1, 14, 16, 17. The data shows thatValproic Acid is released from the polymers 14, 16 and 17 but not frompolymer CE1. Polymer from example CE1 was produced with Valproic Acidattached directly to the incorporating diol, Glycerol, and from twomonomers, Valproic Acid Monoglyceride and HDI, in 1:1 ratio. Polymerexamples 16 and 17 used a linker to distance the Valproic Acid from thepolymer backbone. Polymer example 13 was produced with an additionalpolyester polyol component, PCL.

Comparative Example 2 No Release of Valproic Acid

The polymer described in Example 49 was incubated in phosphate buffer(pH 7.4) at 37° C. for 120 hours. Both Valproic Acid and Valproic AcidMonoglyceride were measured by GC-MS. After 120 hours release of VA-MGcould be detected but not trace of VA was found. The polymer describedin Example 47 was produced from a 1:1 molar ratio of Valproic AcidMonoglyceride and Adipic Acid. As the amount of VA-MG released wasgreater than the amount of VA released from the polymer, such a polymerlies outside the claims of this patent but serves as a comparator to thepolymer claimed within the invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

The invention claimed is:
 1. A biodegradable polyester polymer which isa copolymer of: a monomer—bioactive moiety conjugate of formula (II):

where: X′ and Y′ are each hydroxyl; R represents a linear or branchedoptionally substituted hydrocarbon; Z is a spacer moiety; and D is areleasable bioactive moiety; and at least one selected from the groupconsisting of: (i) an alkyl ester of lysine diisocyanate; and (ii) apolyisocyanate and one or more polyester polyol co-monomers.
 2. Thebiodegradable polymer of claim 1, which is a copolymer of themonomer-bioactive moiety conjugate of formula (II) and (b) an alkylester of lysine diisocyanate.
 3. The biodegradable polymer of claim 2,which is a copolymer of the monomer-bioactive moiety conjugate offormula (II) and an ethyl ester of lysine diisocyanate.
 4. Thebiodegradable polymer of claim 1, which is a copolymer of themonomer-bioactive moiety conjugate of formula (II) and a polyisocyanateand one or more polyester polyol co-monomers.
 5. The biodegradablepolymer of claim 4, wherein the polyisocyanate is selected fromm-phenylene diisocyanate, p-phenylene diisocyanate, 2,4-toluenediisocyanate, 2,6-toluene diisocyanate, 1,6-hexamethylene diisocyanate,1,4-hexamethylene diisocyanate, 1,3-cyclohexane diisocyanate,1,4-cyclohexane diisocyanate, hexahydro-toluene diisocyanate and itsisomers, isophorone diisocyanate, dicyclo-hexylmethane diisocyanates,1,5-napthylene diisocyanate, 4,4′-diphenylmethane diisocyanate, 2,4′diphenylmethane diisocyanate, 4,4′-biphenylene diisocyanate,3,3′-dimethoxy-4,4′-biphenylene diisocyanate,3,3′-dimethyl-diphenylpropane-4,4′-diisocyanate, 2,4,6-toluenetriisocyanate, 4,4′-dimethyl-diphenylmethane-2,2′,5,5′-tetraisocyanate,and alkyl esters of lysine diisocyanate.
 6. The biodegradable polymer ofclaim 1, which is a copolymer of the monomer-bioactive moiety conjugateof formula (II) and an alkyl ester of lysine diisocyanate, apolyisocyanate, and a polyester polyol co-monomer.
 7. The biodegradablepolymer of claim 1, wherein the bioactive moiety (D) is selected from5-alpha-reductase inhibitors, amebicides, aminosalicylates, anaesthetics(general and local), analgesics, angiotensin inhibitors, anorexiants,antacid agents, anti-angiogenic agents, antianginal agents,antiarrythmic agents, antiarthritic agents, antibiotics, antibacterialagents, antibodies, anticoagulants, anticonvulsants, antidepressants,antiepileptic agents, antifungals, anthelmintics, antihistamines,antihypertensives, antihyperlipidemic agents, antiinfectives,antiinflammatories, antiemetics, antimalarial, antimetabolites,antimigraine, antimitotics, antiparasitic agents, antiparkinson agents,antipsychotics, antiprotozoals, antitussives, antiulcer agents,antivirals, anxiolytics, bronchodilators, decongestants andexpectorants, cancer therapy and related pharmaceuticals, cardiovascularpharmaceuticals, central nervous system pharmaceuticals,benzopidazepines, beta-adrenergic blocking agents, bisphosphonates,calcium channel blockers, carbonic anhydrase inhibitors, chemokinereceptor antagonist, coumarins and indadiones, cox-2 inhibitors,contraceptives, cytotoxics, diuretics, diabetes therapies, growthhormones, fertility pharmaceuticals, hematinics, glucose modifyingagents, growth promoters, H2 antagonists, heparin and heparinantagonists, hormone replacement therapies, hemostatics,immunosuppressants, immunostimulants, inotropic agents, interferons,hormones and analogs, impotence agents, kinase inhibitors, laxatives,leukotriene modifiers, macrolides, mast cell stabilizers, musclerelaxants/stimulants, mydiratics, neuromuscular blocking agents, obesitytherapeutics, ophthalmic pharmaceuticals, osteoporosis drugs, paintherapeutics, peptides and polypeptides, peripheral vasodilators,platelet inhibitors/stimulating agents, prolactin inhibitors, proteaseinhibitors, protein therapeutics, proton pump inhibitors,radiopharmaceuticals, respiratory pharmaceuticals, sedatives,spermicides, steroids, smoking cessation agents, statins, stimulants andtranquilizers, sulphonamides, thyroid drugs, urinaryacidifiers/alkalinisers, and vasodilators.
 8. The biodegradable polymerof claim 1, wherein D is coupled through Z to R by an ester, amide,thiol, anhydride, imide, carbonate, peroxide, peroxyester, phosphateester, thioester, sulphate ester, carbamate, azo or boronate estermoiety.
 9. The biodegradable polymer of claim 1, wherein Z is selectedfrom —O—; —C(O)—; and optionally substituted: —OC(O)—C₁₋₁₈alkylene-C(O);—C(O)O—C₁₋₁₈alkylene-C(O)—; —NR^(a)C(O)—C₁₋₁₈alkylene-C(O)—;—C(O)O—C₁₋₁₈alkylene-O—; —O—C₁₋₁₈alkylene-NR^(a)—;—OC(O)—C₁₋₁₈alkylene-NR^(a)—; —C(O)—C₁₋₁₈alkylene-NR^(a)—;—OC(O)—C₁₋₁₈alkylene-O—; —C(O)—C₁₋₁₈alkylene-O—; and—C(O)NR^(a)—C₁₋₁₈alkylene-NR^(a)—, where R^(a) is selected fromhydrogen, C₁₋₁₈alkyl, C₁₋₁₈alkynyl, C₆₋₁₈aryl, C₃₋₁₈carbocyclyl,C₃₋₁₈heteroaryl, C₃₋₁₈heterocyclyl, and C₇₋₁₈arylalkyl.
 10. Thebiodegradable polymer of claim 1, wherein R is a linear or branchedoptionally substituted hydrocarbon having from 1 to 12 carbon atoms. 11.A method for preparing a biodegradable polyester polymer, said methodcomprising the step of polymerising a monomer-bioactive moiety conjugateof formula (II):

where: X′ and Y′ are each hydroxyl; and R represents a linear orbranched optionally substituted hydrocarbon; Z is a spacer moiety; and Dis a releaseable bioactive moiety; with at least one selected from thegroup consisting of: an alkyl ester of lysine diisocyanate; and (ii) apolyisocyanate in the presence of one or more polyester polyolco-monomers.
 12. The method of claim 11, wherein the monomer-bioactivemoiety conjugate of formula (II) is polymerised with an alkyl ester oflysine diisocyanate.
 13. The method of claim 12, wherein themonomer-bioactive moiety conjugate of formula (II) is polymerised withan ethyl ester of lysine diisocyanate.
 14. The method of claim 11,wherein the monomer-bioactive moiety conjugate of formula (II) ispolymerised with a polyisocyanate in the presence of one or morepolyester polyol co-monomers.
 15. The method of claim 14, wherein thepolyisocyanate is selected from m-phenylene diisocyanate, p-phenylenediisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate,1,6-hexamethylene diisocyanate, 1,4-hexamethylene diisocyanate,1,3-cyclohexane diisocyanate, 1,4-cyclohexane diisocyanate,hexahydro-toluene diisocyanate and its isomers, isophorone diisocyanate,dicyclo-hexylmethane diisocyanates, 1,5-napthylene diisocyanate,4,4′-diphenylmethane diisocyanate, 2,4′ diphenylmethane diisocyanate,4,4′-biphenylene diisocyanate, 3,3′-dimethoxy-4,4′-biphenylenediisocyanate, 3,3′-dimethyl-diphenylpropane-4,4′-diisocyanate,2,4,6-toluene triisocyanate,4,4′-dimethyl-diphenylmethane-2,2′,5,5′-tetraisocyanate, and alkylesters of lysine diisocyanate.
 16. The method of claim 11, wherein themonomer-bioactive moiety conjugate of formula (II) is polymerised withan alkyl ester of lysine diisocyanate, a polyisocyanate and a polyesterpolyol co-monomer.
 17. An implantable device comprising thebiodegradable polymer of claim
 1. 18. An ocular implant comprising thebiodegradable polymer of claim 1.